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Restoration of intestinal barrier integrity and function in inflammatory bowel disease (IBD) has been associated not only with a reduced burden of persistent symptoms but also with improved long-term outcomes, prompting growing interest in intestinal barrier healing as a potential new therapeutic target. To date, no clinical trials have specifically evaluated therapies aimed at restoring intestinal barrier function in IBD, and there is currently no consensus on how such trials should be designed or how the intestinal barrier should be assessed. The aim of this initiative was to develop consensus recommendations on the optimal design of clinical trials and the selection of tools to evaluate therapies targeting the intestinal barrier in IBD. A panel of 12 international specialists with recognised expertise in the intestinal barrier and/or IBD clinical trials evaluated statements developed from a systematic literature review. Statements were discussed and anonymously voted on using a modified Delphi methodology. Consensus was predefined as at least 75% agreement among participants. The study was conducted and reported in accordance with the Conducting and REporting of DElphi Studies framework. Fourteen statements reached consensus and were approved. These statements addressed key aspects of clinical trial design, including the role of intestinal barrier assessment as an endpoint, timing of reassessment, protocol requirements and disease-specific considerations. Additional statements focused on the selection and standardisation of tools for intestinal barrier assessment, encompassing imaging-based techniques, functional permeability assays and endogenous biomarkers, as well as considerations for implementation and future research directions. This international consensus provides a structured framework to guide the design of future clinical trials evaluating efficacies of therapies in restoring intestinal barrier integrity and/or function in IBD.

Coupled with well-characterized host genetic and environmental risk factors, alterations of gut microbial communities contribute to risk and severity of inflammatory bowel disease (IBD) and its subtypes, Crohn's disease (CD) and ulcerative colitis (UC). In a rapidly advancing field in which diverse multinational cohorts and molecular methods have been created, highly-resolved microbial traits such as protein function and strain genetics can now be investigated through meta-analysis. We integrated 2,371 stool metagenomes from 542 individuals with IBD and their referent counterparts from the United States, Canada, and Europe, utilizing all seven IBD cohorts in the Human Microbiome Bioactives Resource, which we interrogated using taxonomic, functional, and strain profiling. We systematically identified the mass expansion of pro-inflammatory, oral-predominant taxa in the IBD gut, such as Veillonella and Streptococcus spp. We also accurately discriminate CD from UC, a clinically challenging problem, using highly-resolved microbial strain genetics (AUC=0.69). Further, we observed disease-specific shifts in carbohydrate metabolism, a likely consequence of small bowel dysfunction in CD, but not UC, as well as perturbations in mucin utilization, increased microbial virulence and invasion cassettes, and loss of carnitine degradation pathways in IBD. Finally, we observed novel and significant differences in the gene carriage among both IBD- and non-IBD-associated taxa, suggesting that strain-specific functional variation may contribute to pathogenesis and disease-related bacterial fitness. Microbial clades responsible for IBD-linked dysbiosis are not uniform, and their functionality in IBD and CD/UC subsets are driven by species and strain lineage-specific variants.

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is increasingly recognized not merely as an immune-mediated disorder, but as a systems-level condition arising from dynamic interactions among host genetics, environmental exposures, the gut microbiome, and epigenetic regulation. While genetic susceptibility confers risk, accumulating evidence indicates that epigenetic mechanisms act as molecular integrators that translate environmental and microbial signals into sustained transcriptional programs governing immune tolerance, epithelial integrity and tissue repair. Concurrently, intestinal dysbiosis, characterized by loss of short-chain fatty acid-producing commensals and expansion of pro-inflammatory taxa, reshapes host metabolism and chromatin states through microbial-derived metabolites including short-chain fatty acids, secondary bile acids, and tryptophan catabolites. These metabolites affect epigenetic enzymes and modulate the epigenetic chromatin landscape as well as mitochondrial bioenergetics, linking microbial ecology to inflammatory gene regulation. In turn, epigenetic alterations in epithelial and immune compartments influence antimicrobial defense, barrier function, and cytokine networks, thereby sculpting microbial community organization. This bidirectional microbiome-epigenome dialogue creates self-reinforcing circuits that can either sustain mucosal homeostasis or drive chronic inflammation and colitis-associated tumorigenesis. In this review, we synthesize emerging insights into the microbiome-epigenome-mitochondrial axis in IBD and propose a conceptual framework in which metabolic, microbial, and genome-mediated signals converge to determine disease trajectory. We discuss how this integrative perspective may assist biomarker discovery and therapeutic innovation, including epigenetic modulators and microbiota-targeted interventions. Understanding IBD as a dynamically regulated host-microbe ecosystem may accelerate the development of precision strategies aimed at restoring resilient mucosal equilibrium.

Fusobacterium nucleatum (F. nucleatum) has been increasingly implicated in the pathogenesis of inflammatory bowel disease (IBD), yet the mechanisms underlying its effects remain incompletely defined. In this study, we integrated human fecal and mucosal samples, comparative metabolomics, multiple experimental colitis models, bacterial genetic manipulation, macrophage functional assays, and host signaling analyses to identify a macrophage-centered mechanism through which F. nucleatum exacerbates colitis. We show that F. nucleatum colonization increases intestinal and systemic levels of its metabolite succinic acid, upregulates the expression of its cognate receptor SUCNR1 on intestinal macrophages, activates NF-κB signaling, and promotes pro-inflammatory macrophage activation. This macrophage inflammatory response is associated with epithelial barrier disruption, increased epithelial apoptosis, and aggravated mucosal and systemic inflammation. A fumarate reductase-deficient (frdA-KO) F. nucleatum strain with impaired succinic acid production showed a markedly reduced capacity to activate macrophage NF-κB signaling, induce macrophage inflammatory activation, and aggravate colitis, whereas exogenous succinic acid restored these effects in the frdA-KO setting. Moreover, siSUCNR1 and pharmacological NF-κB inhibition substantially attenuated succinic acid-induced macrophage inflammatory activation, supporting the involvement of a SUCNR1-NF-κB signaling cascade. Collectively, these findings demonstrate that F. nucleatum exacerbates colitis by producing succinic acid and engaging SUCNR1-NF-κB-dependent inflammatory activation of macrophages, highlighting the F. nucleatum-succinic acid-SUCNR1-NF-κB axis as a potential therapeutic target in IBD.

Ulcerative colitis (UC) is an immune-mediated chronic inflammatory bowel disease that severely impairs patients' quality of life. Efficient oral colon-targeted delivery systems are urgently needed to improve local therapeutic efficacy while minimizing systemic exposure. Herein, we developed a pH-responsive Eudragit S100-coated coacervate microdroplet system for the oral delivery of natural Bletilla striata polysaccharide (BSP), termed BSP@EU-Coac. The optimized BSP@EU-Coac microdroplets exhibited a spherical morphology with an average hydrodynamic diameter of 3.86 ± 0.82 μm, an encapsulation efficiency of 85.03 ± 3.66%, and a drug loading capacity of 9.29 ± 0.93%. In vitro release studies showed that BSP@EU-Coac effectively limited premature BSP release under simulated gastric and small intestinal conditions, while achieving pH-triggered sustained release in simulated colonic medium, with a cumulative release of approximately 88.25% within 96 h. In vitro assays further demonstrated that BSP@EU-Coac showed good cytocompatibility at the working concentration and markedly reduced intracellular ROS levels, with ROS fluorescence intensity decreased by 53.95% and 51.13% in RAW264.7 macrophages and Caco-2 cells, respectively. After oral administration, fluorescence imaging confirmed that BSP@EU-Coac preferentially accumulated in the inflamed colon and maintained detectable colonic retention for up to 24 h. In a DSS-induced colitis mouse model, BSP@EU-Coac significantly alleviated UC symptoms, as evidenced by improved body weight recovery, reduced disease activity index, and restoration of colon length from 4.99 ± 1.23 cm in the model group to 8.66 ± 1.92 cm. Mechanistically, BSP@EU-Coac modulated macrophage polarization by reducing the M1-like CD86⁺CD206⁻ population from 29.26% to 8.95% and increasing the M2-like CD86⁻CD206⁺ population to 20.70%, accompanied by suppressed pro-inflammatory cytokine expression, enhanced tight junction protein expression, reduced oxidative stress, and partial restoration of gut microbiota homeostasis. Overall, this study demonstrates that BSP@EU-Coac is a promising oral colon-targeted polysaccharide delivery platform for UC therapy through integrated regulation of oxidative stress, immune response, epithelial barrier repair, and gut microbiota.

Crohn's disease (CD) involves aberrant intestinal T cell immunity and genetic variants associated with disease development. Notably, mutations impairing NOD2 signaling represent the largest genetic risk factor for CD. Paradoxically, although NOD2 variants are associated with CD, its ligand, bacterial muramyl dipeptide, is a potent stimulator of immunity, long recognized as the minimal component required for the adjuvanticity of complete Freund's adjuvant. This paradox highlights a critical gap in our understanding of how NOD2 coordinates the innate-adaptive immune cross-talk required to maintain intestinal homeostasis. Here we show that NOD2 engagement by muramyl dipeptide drives T cell homing to the mesenteric lymph nodes during both homeostasis and infection. This recruitment promotes antigen-specific effector and memory T cell accumulation in the ileal lamina propria, a process essential for effective recall responses and clearance of secondary infection. Mechanistically, this process requires endothelial-intrinsic NOD2 expression, which drives a specialized transcriptional program for leukocyte recruitment.

The pathogenesis of inflammatory bowel disease (IBD) involves a self-perpetuating cycle driven by oxidative stress, microbial dysbiosis, and immune dysregulation. Restoring intestinal microbiota homeostasis and immune balance is therefore critical for intestinal health and long-term disease remission. In this study, an M2 macrophage-based biohybrid system (GaInMg@PDA@M2) was constructed to achieve synergistic intervention against these multiple pathological pathways. This biohybrid system utilized M2 macrophages with inherent inflammatory tropism as delivery vehicles, loaded with multifunctional nanoparticles (GaInMg@PDA) composed of liquid metal (GaIn), magnesium ions (Mg²⁺) and polydopamine (PDA). The nanoparticles effectively scavenged reactive oxygen species and exhibited synergistic antibacterial effects with the GaIn component, while the released Mg²⁺ further promoted macrophage polarization towards the anti-inflammatory M2 phenotype. In a DSS-induced murine colitis model, GaInMg@PDA@M2 demonstrated inflammatory targeting for the diseased colonic tissue and significantly ameliorating clinical symptoms including disease activity index, colon shortening and histopathological damage. The therapeutic mechanisms involved downregulation of pro-inflammatory cytokines, upregulation of anti-inflammatory cytokines, enhancement of antioxidant enzyme activity, restoration of intestinal tight-junction protein expression, and rebalancing of gut microbiota homeostasis. This "cell-homing and multi-effect synergy" strategy represented a precise therapeutic approach capable of disrupting the key pathological cycle in IBD. STATEMENT OF SIGNIFICANCE: Inflammatory bowel disease (IBD) is driven by a self-perpetuating cycle of oxidative stress, microbial dysbiosis, and immune dysregulation, making restoration of intestinal ecosystem balance a major therapeutic challenge. Conventional therapies often lack specificity or fail to address these interconnected pathologies simultaneously, owing to systemic side effects, non-specific immunosuppression, and diminished efficacy over time. In response, a paradigm shift toward a multi-targeted strategy that concurrently tackles oxidative stress, corrects dysbiosis, and resolves inflammation is imperative to break this cycle. To this end, an M2 macrophage-based biohybrid system was developed to achieve synergistic intervention across these key pathological pathways, overcoming the limitations of conventional drugs and enabling simultaneous modulation of multiple core disease mechanisms.

Toll-like receptors (TLRs) are considered general sensors of bacterial encounters. Here, we examined whether other pattern recognition receptors are commonly activated during bacterial infection. TLR-independent interferon (IFN) responses were induced in macrophages in response to diverse bacterial encounters. Of the cytoplasmic receptor families examined, the cyclic dinucleotide (CDN) sensor STING was required for IFN responses to evolutionarily diverse bacteria. Various bacterial CDNs were present in murine tissues; these activated stimulator of interferon genes (STING) after bacteriolysis in phagolysosomes in a manner requiring two CDN transporters. Importantly, bacterial CDNs were increased in colonic biopsies from patients with inflammatory bowel disease. Systemic delivery of dead, CDN-laden bacteria promoted anti-tumor immunity in mice. Detection of diverse CDNs, including pyrimidine-based CDNs, was an evolutionarily conserved feature of STING, with distinct binding modes for purine- and pyrimidine-based CDNs. Thus, a phagocytosis-CDN-STING connection places cytoplasmic sensing as a common outcome of host-bacteria interactions that set the immune tone of a tissue, with implications for host defense.

Inflammatory Bowel Diseases (IBD) are lifelong conditions. Current therapeutic approaches target inflammatory signalling rather than improving barrier permeability or repair. The gut microbiome provides an exciting opportunity for novel drug discovery to leverage its role in healthy gut homeostasis. There is a clear need to identify bioactive molecules within the microbiota that could protect the intestinal barrier. Our group has developed a systematic pipeline using metatranscriptomic data to identify, produce, purify, and test microbial proteins in IBD, pinpointing multiple novel microbiota-derived proteins linked to disease activity. We identified a new microbiota protein (BMG-1), that specifically inhibits human neutrophil elastase, a pathogenic protease in IBD. This protease inhibition allows protection of the intestinal epithelial barrier from permeability and promotes epithelial healing. BMG-1 also reduces colon damage in a mouse model of colitis. Finally, we show that the native BMG-1 protein is not only present in human stool, but also significantly decreased in patients with high IBD activity. These findings demonstrate the gut microbiota can specifically regulate the balance of protease/anti-protease activity in the colon, and this represents a novel therapeutic strategy for IBD.

Regulatory T cells (Tregs) are essential for maintaining immune tolerance. We recently identified chaperone-mediated autophagy (CMA), a selective lysosomal degradation pathway, as a critical regulator of Treg function. Treg activation induces CMA, but this response is markedly diminished with aging. Mice lacking CMA specifically in Tregs develop systemic inflammation, impaired immune tolerance and reduced lifespan. We confirm that CMA is a fundamental mechanism supporting Treg suppressive function as CMA-deficient Tregs are unable to suppress intestinal inflammation in a model of inflammatory bowel disease and fail to block the anti-oncogenic immune response activated in a syngeneic tumor model. Mechanistically, CMA supports metabolic fitness, remodels immune-related protein networks, and promotes degradation of the m6A RNA demethylase FTO, linking lysosomal proteostasis to epitranscriptomic control of IL-2 responsiveness. Restoration of CMA in aged mice improves Treg function, highlighting CMA as a promising therapeutic target for both inflammatory diseases and cancer immunotherapy.

Herein, by integrating benzo[1,2-c:4,5-c']bis([1,2,5]thiadiazole) with strong electron-withdrawing capacity and 4,4'-azanediyldibenzoic acid with strong electron-donating capacity into one donor-acceptor-donor type organic linker, a near-infrared-II (NIR-II) emissive zirconium-tetracarboxylate framework, HIAM-4030, was reported. HIAM-4030 possesses an ftw topology and shows a maximum emission peak at 1052 nm. The HIAM-4030-based nanocomposite exhibits targeted delivery, anti-inflammatory efficacy, and real-time, noninvasive visualization of inflammatory bowel disease via NIR-II fluorescence imaging. This work sheds light on the rational design and construction of luminescent metal-organic frameworks with NIR-II emission behaviors for biomedical applications.

Fluorescence biosensing offers a promising transformative strategy for non-invasively diagnosing diseases, but its deployment for clinical urinalysis is largely hindered by the lack of fluorescent endogenous biomarkers, insufficient detection sensitivity and specificity, and intrinsic urinary fluorescence interference. Here, we report an oral renal-clearable near-infrared II (NIR-II) fluorescent biosensor (termed supraNC@PPADT) as a synthetic exogenous biomarker for early diagnosis and therapeutic efficacy monitoring of ulcerative colitis via in vitro fluorometric urinalysis. The supraNC@PPADT biosensor comprises an Au supra-nanocluster (supraNC) core encapsulated within an acid-resistant but reactive oxygen species (ROS)-responsive poly-(1,4-phenyleneacetone dimethylene thioketal) (PPADT) protective shell. Following oral administration, this biosensor maintains high structural integrity in the healthy gastrointestinal tract and releases renal-clearable ultrasmall Au nanoclusters (Au NCs) via ROS-triggered thioketal cleavage at inflamed intestinal sites. Due to minimized background fluorescence interference, oral gavage of the supraNC@PPADT biosensor enables real-time tracking of inflamed lesions via NIR-II fluorescence imaging in an inflammatory bowel disease (IBD) murine model. We successfully validate this biosensor for early diagnosis and therapeutic efficacy monitoring of IBD in mice via NIR-II fluorometric urinalysis, achieving significantly earlier detection time and higher sensitivity than the clinical fecal calprotectin ELISA assay.

The commensal yeast Candida albicans is a major inducer of human mucosal Th17 cells. How C. albicans drives Th17 cell responses at homeostasis, and whether such responses contribute to inflammatory diseases, remains poorly understood. Here, we showed that C. albicans-reactive Th17 cells targeted a limited set of proteins enriched in fungal extracellular vesicles. At homeostasis, these cells predominantly resided in the oral mucosa. However, T cell receptor profiling revealed shared clonotypes across oral and gut tissues, with C. albicans being a major driver of this repertoire overlap. In patients with Crohn's disease, C. albicans-specific Th17 cells with features of oral priming were enriched in intestinal tissues, where they retained their focused antigen specificity but acquired pathogenic Th17 cell traits. Together, our results reveal a stable, antigen-restricted C. albicans Th17 subset that is shared across mucosal sites and undergoes functional adaptation in the inflamed intestine. These cells represent a potential target for immune modulation in Crohn's disease.

Advanced pancreatic ductal adenocarcinoma (PDAC) often progresses rapidly during chemotherapy despite initial assessments of stable disease or partial response by Response Evaluation Criteria in Solid Tumors (RECIST 1.1), underscoring the limitations of the current methods for predicting short-term progressive disease (PD). To address this, the study developed a spatiotemporal deep learning framework that integrates convolutional and long short-term memory (LSTM) neural networks to dynamically predict PD at the next follow-up visit using serial computed tomography (CT) scans and baseline clinical variables. The model was trained on a retrospective cohort of 243 patients (415 predicted events, defined as temporal sequences for the next follow-up PD prediction) and evaluated across internal, external, and prospective cohorts. The model achieved area under the curve (AUC) values of 0.77, 0.76, and 0.74, respectively. Performance remained robust across chemotherapy regimens (AG or Gemcitabine-based, FOLFIRINOX, and SOXIRI; AUC 0.68-0.79), PD subtypes (target lesion growth vs. new metastases; AUC 0.72 vs. 0.77), and baseline disease stages (locally advanced vs. metastatic; AUC 0.85 vs. 0.71). This framework enables the noninvasive, real-time prediction of imminent PD in advanced PDAC, facilitating timely treatment modification. Its validated generalizability and reliance on routine clinical data underscore its potential for seamless integration into chemotherapy management.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide, and accurate prognostic prediction remains highly challenging due to its marked biological heterogeneity and complex tumor microenvironment. To address this challenge, a histopathomics-based survival prediction system (HPSurv) was developed using histopathological whole-slide images (WSIs) for individualized overall survival (OS) prediction. Within this framework, pathological tissue classification, quantitative characterization of tumor spatial heterogeneity, and a survival Transformer were integrated to enable multi-level representation learning from histopathological data. The system was developed and evaluated in 1020 patients across five independent cohorts. Compared with conventional clinicopathological indicators, significantly improved prognostic performance was achieved across multicenter cohorts (p < 0.05), with a mean C-index of 0.761 and time-dependent AUCs of 0.936, 0.877, and 0.772 for predicting 6-month, 2-year, and 3-year survival, respectively. Subgroup analyses further supported its role as an independent prognostic factor and suggested its potential utility in stratifying patients with respect to ACT-related outcomes. In addition, significant associations with key PDAC molecular pathways were observed, providing biological insights into the model predictions and supporting interpretability. In the study, an interpretable and high-performing artificial intelligence (AI) framework for quantitative modeling of PDAC was established. Objective characterization of tumor heterogeneity and accurate postoperative survival prediction are enabled, with potential value for personalized management in PDAC.

Chemoresistance in pancreatic ductal adenocarcinoma (PDAC) is partly driven by pathological stromal remodeling, yet the underlying mechanisms remain poorly understood. Here, we show that gemcitabine treatment induces tumor cell senescence and activates cancer-associated fibroblasts via the senescence-associated secretory phenotype, leading to progressive fibrotic matrix stiffening. This biomechanical reprogramming engages the mechanosensitive ion channel Piezo1, triggering metabolic rewiring that renders BRG1-positive tumor cells increasingly dependent on NRF2-mediated antioxidant defenses. Piezo1 signaling promotes NRF2 nuclear translocation and its chromatin-remodeling cooperation with BRG1, thereby upregulating SLC7A11-dependent antioxidant programs and suppressing ferroptosis. Notably, the combination of the senolytic agent ABT-263 with the ferroptosis inducer Erastin effectively dismantles BRG1-NRF2-driven gemcitabine resistance, alleviates stromal fibrosis, enhances T-cell infiltration, and suppresses tumor growth in vivo. This senolytic-ferroptosis approach exploits metabolic vulnerabilities in chemotherapy-aged PDAC and provides a mechanistic rationale for stroma-targeted combination therapies.

Pancreatic ductal adenocarcinoma (PDAC) is largely refractory to immune checkpoint blockade, owing to its immunosuppressive tumour microenvironment. Neutrophil extracellular traps (NETs) accumulate in PDAC and correlate with disease progression, yet whether NETs reprogram cancer-associated fibroblast (CAF) heterogeneity and the upstream tumour-intrinsic signals that sustain pathological NETosis remain undefined. To delineate how NETs instruct CAF subtype specification and immunosuppression in PDAC, identify upstream NETosis drivers and evaluate combinatorial therapeutic strategies targeting this axis. Quantitative spatial analysis of human PDAC specimens, NETs-pancreatic stellate cell and patient-derived CAF cocultures, biotinylated DNA pull-down with liquid chromatography-tandem mass spectrometry, live-cell integrin-blocking assays, Cleavage Under Targets and Release Using Nuclease (CUT&RUN) sequencing, orthotopic and hepatic colonisation models, CD8+ T-cell functional assays and single-cell RNA sequencing of an eight-arm therapeutic study were employed. NETs-DNA directly engaged integrin α5β1 (ITGA5) on fibroblasts via its N-terminal domain, initiating a FAK (focal adhesion kinase)/SRC (Src family tyrosine kinase)-YAP (Yes-associated protein)-IL-6 (interleukin-6)-JAK (Janus kinase)/STAT3 (signal transducer and activator of transcription 3) autocrine cascade specifying inflammatory CAF (iCAF) differentiation. Tumour-derived neutrophil gelatinase-associated lipocalin (NGAL), induced by IL-17, drove extracellular signal-regulated kinase (ERK)-reactive oxygen species-mediated NETosis. NETs-reprogrammed iCAFs accelerated tumour growth, hepatic colonisation and CD8+ T-cell exhaustion, with exhausted T cells spatially enriched in iCAF-rich regions. A composite NETs/ITGA5 signature stratified overall survival in patients with PDAC. Single-cell transcriptomics demonstrated that triple therapy (anti-IL-17+AV3+anti-PD-1) shifted fibroblasts from iCAF towards myofibroblastic CAF dominance, restored CD8+ T-cell effector programmes and achieved the greatest tumour suppression and survival benefit. We define an IL-17/NGAL/NETs/ITGA5 axis linking neutrophil-derived extracellular DNA to iCAF specification and immunosuppression in PDAC. Cotargeting IL-17 and ITGA5 synergises with PD-1 blockade, providing a rationale for combinatorial immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States, driven by its aggressive biology and high metastatic incidence at diagnosis. With a 5-year survival rate of just 8%, PDAC remains one of the most lethal cancers. Mutant KRAS, present in more than 90% of cases, serves as a key driver of tumorigenesis and metabolic reprogramming. In this issue of Cancer Research, Thakur and colleagues uncover a novel metabolic adaptation that PDAC cells use to survive therapeutic stress. Their integrated metabolomic and lipidomic analyses show that ERK inhibition-targeting a key KRAS pathway effector-not only disrupts glycolysis and glutamine metabolism but also triggers a compensatory increase in fatty acid oxidation (FAO). This shift occurs through lipophagy, a lysosome-mediated lipid degradation process, rather than cytosolic lipolysis. Mechanistically, ERK inhibition promotes the nuclear translocation of TFEB, which drives the upregulation of FAO and lipophagy genes. This metabolic reprogramming enables PDAC cells to survive KRAS pathway blockade. Importantly, cotargeting FAO alongside ERK or KRAS inhibitors elicits a potent synergistic antitumor effect in vivo. This dual-target strategy holds promise for overcoming PDAC resistance to KRAS-targeted therapies, laying the groundwork for novel combination treatments. See related article by Thakur et al., p. 3519.

The tumor microenvironment (TME) actively contributes to pancreatic ductal adenocarcinoma (PDAC) pathogenesis through dynamic bidirectional tumor-stroma interactions. In this study, we demonstrated that ATM-deficient tumor epithelium reprograms the TME in a genotype-specific manner to enhance cancer aggressiveness. In genetically engineered mouse models, pancreatic stellate cell and cancer-associated fibroblast (CAF) coculture systems, single-nucleus multiomics, and human PDAC models, tumoral loss of ATM serine/threonine kinase drove CAFs toward αSMA+ myofibroblastic (myCAF) differentiation, independently of p53 status. The myCAFs, in turn, promoted cancer aggressiveness and chemoresistance. Mechanistically, ATM deficiency increased reactive oxygen species and contractility signaling, enhancing TGFβ1 secretion. Pharmacologic TGFβ inhibition reversed myCAF differentiation, sensitized tumors to chemotherapy, and impaired tumor progression in both murine and human ATM-null models. These findings reveal that ATM-deficient tumors shape a cancer-promoting niche via TGFβ signaling and identify dual targeting of intrinsic and extrinsic vulnerabilities as a promising precision oncology strategy. TGF-β-driven myofibroblastic stromal differentiation in ATM-deficient pancreatic cancer generates a genotype-specific tumor microenvironment, providing a targetable axis and highlighting the need to integrate epithelial genotype and stromal context in pancreatic cancer therapy.

Pancreatic ductal adenocarcinoma (PDAC) carries an extremely poor prognosis, in part resulting from cellular heterogeneity that supports overall tumorigenicity. Cancer-associated fibroblasts (CAF) are key determinants of PDAC biology and response to systemic therapy, and multiple CAF subtypes have been defined. However, defining the effects of patient-specific CAF heterogeneity and plasticity on tumor cell behavior is required to better characterize the role of CAFs in PDAC. In this study, we used multiomic analyses to characterize the tumor microenvironment (TME) in tumors from patients undergoing curative-intent surgery for PDAC. In these same patients, matched tumor organoid and CAF lines were established to functionally validate the impact of CAFs on the tumor cells. CAFs promoted epithelial-mesenchymal transition and a switch in tumor cell classification from classical to basal subtype. Furthermore, CAF-specific interleukin 8 functioned as a modulator of tumor cell subtype. Finally, neighborhood relationships between tumor cells and T cell subsets were defined, demonstrating a distinct spatial coordination among CAF and tumor cell subtypes. Overall, this study provides data supporting CAF signaling as a regulator of the cellular and behavioral heterogeneity in the PDAC TME. These findings can be used to explore rational approaches to improve therapies for this difficult-to-treat disease. Multidimensional analyses highlight the diverse role of cancer-associated fibroblasts in influencing cells in the tumor microenvironment and provide a platform for evaluating emerging therapeutic approaches and studying mechanisms dictating tumor behavior.

The output signal of the sensor is closely correlated with its detection sensitivity, while the selection of luminescent materials and the presence of interfering substances in the detection medium can both affect the output signal. In this study, a bifunctional peptide (HWRGWVDEDKDKDKC) with antibody targeted fixation and interface anti-adsorption properties was designed by integrating recognition (HWRGWV), charge neutralization (DE), antifouling (DKDKDKDK) and anchoring (C) fragments, which endowed the constructed biosensing interface with high target capture efficiency and good antifouling ability. At the same time, AuAgTb-MOF with multiple synergistic amplification effects was developed as luminophore. Concretely, the antenna effect of 3,5-dicarboxyphenylboronic acid to Tb3+, the catalysis of Ag NPs for S2O82- and the conductivity of Au NPs significantly prompted the luminescence of AuAgTb-MOF. The design of intramolecular self-enhanced AuAgTb-MOF not only reduced energy transfer losses, but also simplified the construction of the biosensing platform. On this basic, the constructed biosensor had a wide detection range of 10-4 to 103 U/mL and a low limit of detection of 3.38 × 10-5 U/mL (IUPAC standard), realizing the sensitive and precise detection for pancreatic cancer markers, thus providing a positive reference for the clinical diagnosis of pancreatic cancer.

Cancer-associated fibroblasts (CAFs) are principal determinants of pancreatic ductal adenocarcinoma (PDAC) progression. CAFs can shape tumor behavior via multiple pathways, underscoring the need for a complete understanding of the regulatory mechanisms that govern CAF function. Here, we identified N6-methyladenosine (m6A) remodeling as a hallmark of CAF activation and defined a critical role for the m6A demethylase ALKBH5 in PDAC metastasis. Activated CAFs exhibited a global reduction in m6A abundance, with ALKBH5 emerging as a key regulator of the CAF epitranscriptome. Functionally, CAF-derived ALKBH5 enhanced pancreatic cancer cell migration and invasion in vitro and promoted epithelial-mesenchymal transition-associated gene expression in tumor cells in an m6A-dependent manner. Orthotopic co-implantation models and host genetic ablation models demonstrated that ALKBH5 plays a critical role in metastatic dissemination, with minimal impact on primary tumor growth. Mechanistically, ALKBH5 enhanced the m6A-dependent translation of HSF1 in CAFs, at least in part by relieving IGF2BP3-associated translational constraints. Elevated HSF1 subsequently activated LIF transcription through distal enhancer elements, establishing an ALKBH5-HSF1-LIF signaling axis that mediated the pro-metastatic CAF-tumor cell communication. Clinically, enrichment of ALKBH5⁺HSF1⁺ CAFs independently predicted poor prognosis and was preferentially observed in metastatic PDAC. Collectively, these findings uncover a CAF-intrinsic epitranscriptomic program that drives PDAC metastasis and highlight stromal m6A regulation as a potential therapeutic vulnerability.

Endoscopic screening for gastric cancer reduces mortality, but the optimal upper age limit and modifying role of comorbidity remain unclear. This nationwide retrospective cohort study used the Korean National Health Insurance Service database linked to national mortality records. Individuals aged ≥40 years who underwent screening esophagogastroduodenoscopy between 2005 and 2010 were included and propensity score-matched to non-screened controls. The primary outcome was gastric cancer-specific mortality. Comorbidity was assessed using the Charlson Comorbidity Index (CCI). Hazard ratios (HRs) were estimated in the matched cohort. Among 555 904 propensity score-matched individuals (277 952 per group), gastric cancer-specific mortality HRs showed an age-dependent gradient: <1.0 at 50-59 years (HR 0.56, 95%CI 0.34-0.92), 60-64 (0.65, 0.40-1.07), and 65-69 (0.82, 0.58-1.17); close to 1.0 at 70-74 (0.99, 0.75-1.30) and 75-79 (0.92, 0.68-1.24); and elevated at ≥80 years (2.21, 1.49-3.27). Comorbidity further modified this association: HRs were <1.0 in individuals with CCI <3 (0.86, 0.74-1.01) but elevated in those with CCI ≥3 (1.88, 1.42-2.49). In age-CCI analyses, point estimates favored screening across age groups up to age 75-79 years among individuals with CCI 0, but HRs exceeded 1.0 in most age groups with CCI ≥3. Post-endoscopy respiratory or cerebrocardiovascular events increased with age and comorbidity. The mortality benefit of gastric cancer screening endoscopy diminished with advancing age and comorbidity burden, becoming questionable beyond age 70. At age ≥80 or in individuals with substantial comorbidity, potential harms may outweigh benefits.

Identifying high-risk patients for recurrence after endoscopic resection (ER) of T1 colorectal cancer (CRC) remains challenging. This study aimed to identify recurrence-risk subtypes and develop an interpretable risk stratification framework. This retrospective study analyzed 1123 patients with T1 CRC treated with ER alone across 27 Japanese institutions (July 2009-December 2016). Patients were divided into development (68%) and evaluation (32%) cohorts based on institutional stratification. K-means clustering was applied to clinicopathological variables to identify recurrence-risk subtypes. A decision tree classifier was subsequently developed to generate transparent risk stratification rules. Three distinct subtypes were identified in the development cohort. Subtype 1 exhibited a numerically higher recurrence rate (5.4%) than subtype 2 (0.9%) and subtype 3 (1.4%). Although subtypes 2 and 3 showed comparable recurrence rates, they were clearly differentiated by morphology (flat vs. polypoid). In the evaluation cohort, subtype 1 continued to show a numerically higher recurrence (4.8%) compared with subtypes 2 (1.6%) and 3 (1.1%). The decision tree model stratified recurrence risk hierarchically: submucosal invasion <1,000μm indicated low risk, whereas invasion ≥1,000μm required morphological assessment, with polypoid lesions classified as high risk and flat lesions further stratified using a 2,000μm threshold. Three clinically distinct recurrence risk subtypes were identified in T1 CRC following ER, suggesting that morphological subclassification of T1b lesions may refine stratification beyond conventional depth-based criteria. The decision framework offers a preliminary exploratory basis for recurrence risk assessment in this population.

Computer-aided diagnosis (CADx) may support optical diagnosis of diminutive (≤5 mm) colorectal polyps, replacing histopathology. We described CADx usage and diagnostic performance under real-life, discretionary adoption. This prospective implementation study enrolled patients undergoing colonoscopy at our tertiary center (2021-2025). Patients aged <40 years, with inflammatory bowel disease, polyposis syndromes, or no diminutive polyp were excluded. CADx use was at the endoscopists' discretion. Endoscopists' optical diagnoses with and without CADx assistance, and the CADx output were documented. Main outcomes were CADx usage and sensitivity for adenomas of CADx-assisted and CADx-unassisted optical diagnosis, using histopathology as reference. 868 patients (age 66.1 years, 47.0% female) with 1660 diminutive polyps (62.0% adenomas) were included. Endoscopists recorded CADx-assisted and CADx-unassisted optical diagnoses for 657 and 864 polyps, respectively, showing sensitivity of 85.1% (95%CI 78.3-90.1) and 85.1% (81.2-88.4), specificity 55.2% (45.8-64.3) and 61.1% (54.5-67.3), positive predictive value 76.2% (69.1-82.1) and 79.3% (75.5-82.9), negative predictive value (NPV) 60.8% (52.6-68.5) and 67.1% (60.7-73.0), and accuracy 62.7% (56.5-68.4) and 66.4% (63.0-69.7), respectively. In a simulated resect-and-discard strategy, CADx assistance marginally increased the proportion of polyps that could avoid histopathology (84.9% vs. 81.1%). For high-confidence rectosigmoid diagnoses, NPV for adenomas was 95.5% (86.9-98.5) for CADx-assisted and 93.8% (85.9-97.4) for CADx-unassisted predictions. Both CADx-assisted and CADx-unassisted optical diagnoses showed good diagnostic performance in real-world practice. Assessment of the relationship between CADx use and optical diagnosis was limited by unavoidable selection bias relating to discretionary use and variable endoscopist behavior.

Hepatic venous pressure gradient (HVPG) is the gold standard for assessment of prognosis in compensated advanced chronic liver disease (cACLD), yet its invasiveness limits broad clinical use. We developed and validated the Cirrhosis Risk Identifier (CIRI) model, a machine-learning tool using 11 demographic and routine laboratory parameters trained to prognosticate first decompensation; and benchmarked its performance against HVPG, liver stiffness measurement (LSM), FIB-4 and MELD. cACLD patients were identified in the U.S. Optum Clinformatics Data Mart (Optum CDM) for model development and internal validation and externally validated in a prospective European tertiary care cohort. The primary endpoint was first decompensation (ascites, encephalopathy, variceal bleeding) with HCC and death as competing events. CIRI was trained on 112,618 and internally validated on 18,852 cACLD patients in Optum CDM, with 210 HVPG-characterized cACLD patients (European cohort) included for external validation. In both Optum CDM and Europe, steatotic liver disease was the leading etiology (54%; 44%), with median follow-up of 18.5 months (IQR 7.2-40.4) and 27.5 months (21.2-34.8), respectively. In Optum CDM, CIRI showed higher 1- and 2-year time-dependent AUROCs (0.816, 0.815) than MELD and FIB-4 (both p<0.001). In Europe, AUROCs (0.836, 0.769) were comparable to HVPG (both p>0.900) and superior to LSM (both p<0.05). CIRI predicted decompensation independently (Optum CDM: adjusted subdistribution hazard ratio [aSHR]: 1.67, p<0.001; Europe: aSHR: 1.66, p=0.017) with a cutoff of ≥-8.25 identifying patients at comparable decompensation risk as HVPG ≥10mmHg (CSPH). The machine-learning-based CIRI model yielded robust prognostic performance and accurate risk stratification in cACLD patients. CIRI's discrimination of decompensation risk was comparable to that of HVPG, highlighting its potential future utility to non-invasively identify "at-risk" cACLD patients. NCT03267615 IMPACT AND IMPLICATIONS: Hepatic decompensation marks the key clinical transition from compensated to decompensated advanced chronic liver disease and is associated with substantially worse prognosis. However, current risk assessment remains limited by the invasiveness of the gold-standard hepatic venous pressure gradient (HVPG) measurement and the infrastructure required for established non-invasive tests such as liver stiffness measurement (LSM). In this study, we developed and validated "Cirrhosis Risk Identifier" (CIRI), a machine-learning model based solely on routine laboratory and demographic data, which predicted first hepatic decompensation with performance comparable to HVPG and superior to widely used non-invasive tests including LSM, MELD and FIB-4. These findings are important for clinicians and researchers aiming to identify patients with cACLD who are at increased short-term risk of hepatic decompensation. Pending further prospective validation, CIRI could support scalable and repeatable risk stratification and help guide surveillance intensity and targeted strategies intended to prevent hepatic decompensation for high-risk patients.

Oral anticoagulants may reduce risk of hepatic decompensation in patients with compensated cirrhosis, but well-powered randomized trials are missing. We aimed to estimate the effect of oral anticoagulants on risk of hepatic decompensation and major bleeding in patients with compensated cirrhosis and atrial fibrillation. Observational data from Swedish healthcare registers 2011-2022 were used to emulate a target trial of oral anticoagulants in patients with compensated cirrhosis and newly diagnosed atrial fibrillation. Inverse-probability weighted marginal structural models were used to compare 5-year risks of hepatic decompensation and non-portal hypertension-related major bleeding in initiators versus non-initiators of oral anticoagulants. The study included 1,160 patients (715 men [61.6%]; median [p25-p75] age of 73 years [67-79]). The 5-year risk of hepatic decompensation was 10.4% (33/383) in initiators and 16.6% (112/777) in non-initiators (risk ratio [RR]=0.62, 95% confidence interval [CI]=0.33-0.92), corresponding to a number needed to treat of 17 (95%CI=9-112). The risk reduction was primarily driven by a reduced risk of ascites (RR=0.58, 95%CI=0.26-0.90). The risk of major bleeding was 19.0% (63/383) in initiators and 19.8% (149/777) in non-initiators (RR=0.96, 95%CI=0.64-1.28). Risks were similar between treatment groups regarding fatal, intracranial, gastrointestinal, and other bleedings. In this nationwide observational study, patients with compensated cirrhosis and atrial fibrillation who initiated oral anticoagulants had lower risk of hepatic decompensation, and similar risk of major bleeding compared to non-initiators. The results suggest oral anticoagulants are safe in patients with compensated cirrhosis and may improve prognosis. Randomized trials are warranted to confirm these results.

Non-selective beta-blockers (NSBB) are widely used to prevent decompensation in cirrhosis. Guidelines recommend discontinuing NSBB in patients with cirrhosis and acute kidney injury (AKI), although based largely on expert opinion and limited evidence. We evaluated the impact of NSBB on AKI outcomes in patients with cirrhosis. This multicenter study enrolled patients hospitalized for decompensated cirrhosis and AKI. Data on NSBB treatment, type and dose and continuation/discontinuation/tapering were collected. Outcomes were compared between patients receiving and not receiving NSBB and between those who discontinued/tapered and those who did not. Inverse probability of treatment weighting (IPTW) balanced demographics, liver disease severity, hemodynamic parameters, AKI stage and acute-on-chronic liver failure (ACLF) grade. Main outcomes were AKI resolution and 28-day mortality. Out of 1,238 patients with AKI, 503 were on NSBB (propranolol 55%; carvedilol 45%). After IPTW adjustment, NSBB treatment at AKI diagnosis was associated with higher likelihood of AKI resolution (sHR=1.29 [95% CI=1.12-1.48], p<0.001) and reduced 28-day mortality (sHR=0.70 [95% CI=0.55-0.91], p=0.006). At 48-72 hours from AKI diagnosis, NSBB were continued in 122 patients (24%) and discontinued/tapered in 349 (69%); 4 patients died, and data were not available for the remaining 28 patients. After excluding patients in whom NSBB continuation was not clinically feasible (n=59), IPTW-adjusted analysis showed no evidence of an association between NSBB continuation and AKI resolution (sHR=0.84 [95% CI=0.57-1.25], p=0.391) or 28-day mortality (sHR=0.51 [95% CI=0.23-1.11], p=0.089). NSBB use at AKI diagnosis was associated with improved renal recovery and survival in patients with acutely decompensated cirrhosis and AKI. Continuation during hospitalization does not appear harmful, supporting careful individualized management rather than systematic withdrawal. Owing to potential adverse hemodynamic effects, current guidelines recommend discontinuation of non-selective beta-blockers (NSBB) in patients with Acute Decompensation (AD) of liver cirrhosis and Acute Kidney Injury (AKI). However, this recommendation relies largely on expert opinion, since robust clinical evidence is lacking. This study prospectively evaluated the impact of NSBB on AKI outcomes in a large multicentre cohort of patients with AD and AKI. Treatment with NSBB at AKI diagnosis was associated with greater likelihood of AKI resolution and lower risk of 28-day mortality, while no evidence of an association between early discontinuation and improved outcomes was observed. These findings support a personalized approach to NSBB management in decompensated patients with AKI and highlight the need to identify patients who may benefit most from NSBB discontinuation.

The 2023 multisociety Delphi consensus redefined the nomenclature for steatotic liver disease (SLD) by replacing nonalcoholic fatty liver disease (NAFLD) with metabolic dysfunction-associated steatotic liver disease (MASLD) and introducing metabolic dysfunction and alcohol-associated liver disease (MetALD) and alcohol-associated liver disease (ALD). This revised framework is expected to enhance epidemiological surveillance, phenotyping of SLD, and public health interpretation. This review summarizes contemporary literature on the global epidemiology, disease burden, and comparative outcomes of MASLD, MetALD, and ALD. MASLD remains the most prevalent SLD subtype, affecting approximately 30%-40% of adults worldwide, with a rising burden over time. MASLD rapidly increases in regions with lower sociodemographic indices. MetALD affects an estimated 2%-8% of adults and represents an important overlap phenotype, although its prevalence is likely underestimated due to frequent underreporting of alcohol intake. ALD has a lower prevalence but contributes disproportionately to higher liver-related morbidity and mortality and is reported to have a marked regional variation linked to patterns of alcohol consumption. SLD has emerged as a major global epidemic, with MASLD imposing the greatest population burden and MetALD/ALD disproportionately contributing to severe liver-related outcomes. Across SLD phenotypes, cardiovascular disease is a major cause of death in non-cirrhotic disease, while liver-related outcomes show a gradient associated with alcohol exposure. Significant epidemiologic limitations include heterogeneity in the steatosis assessment methods, limited availability of cardiometabolic criteria, and reliance on self-reported alcohol consumption. Mitigating this growing burden of SLD requires public health policies that incorporate metabolic risk prevention, regulation of alcohol consumption, and early risk stratification.

Urolithin A (UroA), a gut microbiota-derived metabolite of ellagitannins, has diverse biological activities but suffers from low water solubility and poor bioavailability. To address these challenges, this study developed gum arabic (GA)-coated UroA liposomes (UA-LPs-GA). The GA coating significantly enhanced the encapsulation efficiency, stability, and bioaccessibility of UroA. Pharmacokinetic studies showed that UA-LPs-GA improved the relative oral bioavailability of UroA by 3.09-fold compared to free UroA. In a high-fat diet-induced mouse model of non-alcoholic fatty liver disease (NAFLD), UA-LPs-GA administration effectively alleviated key pathological features, including hepatic steatosis, inflammation, and oxidative stress, with superior efficacy to free UroA. Mechanistic studies revealed that the hepatoprotective effects were mediated through activation of the AMPK/Nrf2 signaling pathway. Additionally, UA-LPs-GA positively modulated the intestinal flora, enriching beneficial bacteria and suppressing harmful taxa. This study establishes a practical approach to enhance UroA delivery and provides a new strategy for using functional polysaccharides in advanced delivery systems for NAFLD management.

While gasdermin (GSDM)-mediated pyroptosis is a potent immune effector, its antiviral potential remains largely untapped. Here, we introduce viral protease-initiated lytic cell death (VID), a universal mRNA therapeutic platform inspired by the modular architecture of GSDM and the clinical success of mRNA vaccines. By engineering gasdermin-D (GSDMD) to harbor viral protease-specific cleavage motifs, we generated VID activators (VIDAs) that selectively trigger lytic cell death in virus-infected cells. Using hepatitis A virus (HAV) as a model, lipid nanoparticle (LNP)-encapsulated VIDA mRNA abolished viral replication and shedding in vivo and mitigated liver injury through a coordinated "kill-and-alert" mechanism that primes bystander immunity. The platform's versatility was further demonstrated against Zika virus (ZIKV) and SARS-CoV-2. Leveraging a generative artificial intelligence (AI) framework, we designed de novo cleavage motifs for the SARS-CoV-2 main protease, yielding optimized VIDAs with superior antiviral potency. Collectively, our study establishes VIDA mRNA as a versatile, broadly applicable strategy for combating diverse viral threats.

The prevailing notion is that effector T cell activation mediates anti-PD-1 efficacy in cancer. Here, we conducted a mechanistic study parallel to our phase 2 trial of perioperative anti-PD-1 therapy in patients with resectable recurrent hepatocellular carcinoma (HCC) (NCT04615143) to study its mechanism of action. Late-recurrence patients present two distinct subtypes characterized by T cell or B cell dominant responses in the tumor microenvironment by dynamic single-cell multi-omics analysis. Clonal antibody repertoire analysis and spatially paired scRNA-seq/BCR-seq reveal somatic hypermutation promoting antibody binding against hepatitis B virus core antigen (HBcAg) within tumor tertiary lymphoid structures (TLSs) in these type B-late recurrence patients. Mechanistically, HBcAg is exported into the extracellular space, triggering local B cell and antibody responses and complement activation. In mice, these high-affinity HBcAg-reactive antibodies lead to complement-mediated antitumor activity with enhanced anti-PD-1 efficacy. Thus, we uncover enhanced anti-virus B cell immunity within the TLS as a mechanism to anti-PD-1 in HCC.

Robotic assistance may mitigate occupational hazards associated with endoscopic retrograde cholangiopancreatography (ERCP). We evaluated the safety, feasibility, and learning curve of a new ERCP robotic system. In this observational study, 26 patients with common bile duct stones underwent robotic-assisted ERCP; 6 underwent biliary cannulation only and 20 underwent stone extraction. For the 20 cases with stone extraction, comparisons were performed using 1:1 propensity score matching (PSM) with conventional ERCP performed by the same operator. The safety outcome was adverse events. Feasibility outcomes included technical success, procedural times, operator radiation exposure, and learning-curve characteristics. After PSM, adverse event rates were similar between groups. Post-ERCP pancreatitis occurred in 15.0% (3/20, robotic) and 10.0% (2/20, conventional) (P >0.99), with no bleeding, perforation, or procedure-related mortality. Biliary cannulation and stone extraction success rates were 100% (20/20) in both groups. Robotic-assisted ERCP had a longer procedure time (36.6 vs. 17.0 minutes; P < 0.001), but similar cannulation and fluoroscopy times. In robotic-assisted procedures, radiation exposure was markedly lower in the control room than in the operation room (0.10 vs. 1.26 μSv; P < 0.001). Learning-curve analysis suggested performance stabilization after 10-12 cases. Robotic-assisted ERCP appeared safe and feasible, with high technical success and substantially reduced operator radiation exposure.

Metabolic disorders induced by a high-fat diet (HFD) represent a major global health burden. Natural polysaccharides possess lipid-lowering activity, but their high molecular weight often limits bioavailability. In this study, a low-molecular-weight polysaccharide, EMIP, was prepared through the enzymatic degradation of Morchella importuna polysaccharide (MIP). EMIP exhibited significantly enhanced antioxidant and pancreatic lipase inhibitory activities in vitro. In HFD-fed mice, EMIP more effectively reduced serum and hepatic lipid levels, improved liver function, and alleviated oxidative stress and inflammatory responses. Multi-omics analysis further revealed that EMIP modulated the gut microbiota (e.g., enriching Lactobacillus and reducing Dubosiella) and regulated key liver metabolites such as lyso-phosphatidylglycerol, lyso-phosphatidylcholine, and 8-aminooctanoic acid-a novel potential biomarker for lipid metabolism disorders. KEGG pathway analysis indicated that EMIP regulated lipid metabolism via pathways related to amino acids and hormones, providing new insights into the intervention of metabolic syndrome with functional polysaccharides.

Somatostatin (SRIF) and its receptors (SSTR) are key players in the regulation of neuroendocrine neoplasms (NEN), with significant implications for diagnosis, prognosis, and treatment. The field of SSTR-targeted drugs/ligands (SRLs) is continuously evolving, with emerging novel therapeutic approaches aiming to address the numerous unmet needs and limitations of the standard-of-care (SOC) SRLs. In the present manuscript, we aim to provide a concise review of the field, focusing on the new and ongoing developments and potential novel approaches to be considered in the future. The paper (1) provides insights into the pathophysiology of SSTR in relation to unmet needs in the SRL efficacy and limitations, (2) presents a state-of-the-art assessment of knowledge on the SOC SRLs, and (3) depicts current ongoing and future research, highlighting areas of insufficient knowledge for SRLs in NEN routine practice.

1: Before commencing hands-on upper gastrointestinal bleeding (UGIB) training, trainees should have thorough knowledge of: pathology, vascular anatomy, technical use of devices, clinical care pathways, and all relevant components of pre-, intra-, and postprocedural patient care. 2: Preadoption technical skills required for training in the management of UGIB include adequate scope handling, intubation technique, washing and suctioning of residue, mucosal examination, and handling of accessories. 3: Preadoption technical skills required for training in the management of UGIB should be assessed individually based on a competency framework and not solely on numerical thresholds. 4: The integrative skills required for the management of UGIB do not essentially differ from those needed in other endoscopic procedures and should include adequate situational awareness, collaboration, team leadership, and patient communication in order to ensure short- and long-term goals are achieved. 5: The trainee should reach minimum recommended standards for key performance indicators in upper GI endoscopy before starting training in the management of UGIB. 6: Attendance of at least one half-day training session on a dedicated simulator that provides GI bleeding training at the beginning of training for management of UGIB is advised. 7: Trainees should be supervised directly and carefully during UGIB training for a minimum of 20 procedures with endoscopic stigmata of recent hemorrhage in order to prevent failure of hemostasis and ensure adequate trainee skill acquisition. 8: Trainers should take into account pre-endoscopic and intraprocedural factors predicting outcome, technical complexity, and risk of hemostatic failure when deciding appropriateness and degree of trainee involvement in case management. 9: During their training, trainees should be exposed to all hemostatic modalities, as per ESGE guideline recommendations, and the opportunities for teaching arising from the specifics of each UGIB case. 10: Trainers should use "successful hemostasis," defined as the absence of any further bleeding (persistent or recurrent bleeding), as the ultimate goal of training in the endoscopic management of UGIB. 11: Patients with recurrent bleeding should be treated by experienced endoscopists or by a trainee under their direct supervision owing to the higher risk of failure of conventional endoscopic treatment. 12: Trainers who are teaching management of UGIB should fulfil the same standards as any trainer of basic endoscopy procedures. 13: Trainees should be exposed to multidisciplinary team discussions and care pathways for failed endoscopic treatment of UGIB. 14: Training centers with limited UGIB case volumes are encouraged to offer short-term immersive training in centers with high volume caseloads of UGIB in order to ensure sufficient exposure for trainees. 15: Competency in managing UGIB is defined as the ability to assess the need for endoscopy, and plan and carry out successful hemostasis. 16: Trainees should manage an indicative number of 30 cases in which successful hemostasis is achieved before evaluation of competence in management of UGIB. 17: UGIB-CAT is advised as a formative assessment tool during training to track acquisition of competence and provide trainee feedback. 18: Trainees should undergo a formal summative assessment of competence in managing UGIB during their training. 19: Endoscopists should continue a period of tracking results and mentored practice with an experienced colleague for at least 6 months after achieving competence in managing UGIB. 20: As trainees move to independent practice, they should have established access to or referral pathways for key supporting specialties involved in the nonendoscopic management of acute UGIB (including emergency medicine, surgery, and interventional radiology).

Despite recent progresses in microbiome and infection, the role of multi-kingdom gut microbiome in kidney transplantation (KT) infection remains unexplored. Here we performed a longitudinal and integrative multi-omics analysis of the gut microbiome, fecal metabolome and plasma metabolome in 169 KT recipients across 5 different transplantation centers, comprising discovery and validation cohorts. We observed KT-specific four kingdom microbiome dysbiosis, including bacteria, fungi, archaea and viruses, with the most pronounced shifts in bacterial and fungal communities. Furthermore, we identified 6 infection-associated co-abundance groups (CAGs) composed of 23 bacterial and 3 fungal species, highlighting extensive bacterial-fungal interactions. Interestingly, infection-associated fecal metabolomic pattern F1, enriched in N-acetylputrescine and hydroxyproline, was positively correlated with Enterococcus-, Citrobacter- and Lactococcus-dominated CAGs, as well as the plasma metabolite signature, represented by phenylacetyl-l-glutamine, indoxyl sulfate and leukotriene. In contrast, cholesterol sulfate and menadione in plasma were aligned with fecal indoleacetic acid and stachyose, a metabolic signature more characteristic of non-infected recipients. Finally, the combinatorial biomarkers of fungal and bacterial species achieved powerful diagnosis ability of KT infection in an independent validation cohort (area under the receiver operating characteristic curve (AUROC) = 0.80) with the fecal metabolites achieving high accuracy (AUROC = 0.83). Collectively, our findings not only uncovered the postoperative infection-specific multi-kingdom microbial network dynamics, but also revealed the microbial and its metabolic biomarkers with powerful diagnostic ability for postoperative infection in kidney transplantation.

Fecal microbiota transplantation (FMT) has shown promise in overcoming resistance to immune checkpoint inhibitors (ICIs) in early-phase cancer trials. We investigated the safety, feasibility and efficacy of FMT from ICI responders to patients with advanced cancers progressing on ICIs. This was a single-arm phase IIa basket trial (MITRIC; NCT05286294) including patients with ICI-refractory cancer. Long-term ICI responders were used as FMT donors. Patients received FMTs in combination with ICIs; two FMT administrations (by colonoscopy) were scheduled before the first radiological evaluation after 6 weeks, and up to three later FMTs were allowed (by enema). Co-primary endpoints were the evaluation of FMT-related adverse events and objective response rate. Feasibility, clinical benefit rate, progression-free survival (PFS), overall survival (OS), implant engraftment, immune response and biomarkers were among the secondary objectives. The study enrolled 12 patients with melanoma (n=9), head and neck squamous cell carcinoma (HNSCC; n=1), renal cell carcinoma (n=1) or microsatellite instability-high pancreatic cancer (n=1). FMT was well tolerated, whereas immune-related toxicity occurred in 6/12 patients. All patients received the first FMT; 10/12 patients also underwent the second FMT. No objective responses were observed, while 5/12 patients recorded stable disease. Clinical benefit per-protocol (stable disease >6 months) was achieved in a patient with melanoma, who had regression of some lesions and remains alive after 33 months without further systemic treatment. Mixed responses with regression of some lesions were observed in another melanoma patient, and in a patient with HNSCC. The median PFS was 1.5 months, and median OS was 10.1 months. Sequencing of fecal samples indicated engraftment after the first FMT in most patients. Mass cytometry analysis of peripheral blood cells suggested that an activated and differentiated T-cell signature was associated with improved PFS and OS, while a naïve T-cell phenotype and a myeloid-dominant environment were unfavorable. CD14+ monocytes and serum interleukin-8 increased at group level over time. FMT in combination with ICIs was safe and feasible in patients with advanced cancers, but with limited clinical activity. Further studies are required to clarify the potential benefit of FMT, identify the appropriate patient population and define criteria for donor selection. NCT05286294.

Alcohol-associated liver disease (ALD) is a major driver of morbidity and mortality globally, especially in its most severe phenotypes, including alcohol-associated hepatitis (AH), decompensated cirrhosis, and hepatocellular carcinoma. With no US Food and Drug Administration-approved therapies to improve ALD, there is an unmet clinical need to better define the pathophysiology of early and severe liver disease. Recent improvements in preclinical models have furthered our understanding of the mechanisms of disease in advanced ALD. In this review, our focus is on current progress in identifying therapeutic targets utilizing preclinical models and reporting the rationale for and current status of ongoing clinical trials that aim to develop effective therapies to slow the progression of earlier stages of ALD and especially improve survival in severe AH.

Lifestyle modification is a well-established approach for improving metabolic health and reducing ectopic fat accumulation in the liver. The Melbourne Consensus has recently highlighted intrapancreatic fat deposition (IPFD) as an important fat depot, playing a key role in the development of both endocrine and exocrine pancreatic diseases. Nevertheless, the existing literature on the impact of lifestyle modification on IPFD has not been systematically synthesized. We conducted a comprehensive systematic review and meta-analysis to assess the effects of lifestyle modification on IPFD. A systematic literature search was conducted in PubMed and Embase databases to identify interventional studies evaluating the effects of lifestyle modification on IPFD measured by magnetic resonance-based techniques. Data were meta-analyzed using a random-effects model. Statistical heterogeneity was assessed using the I² statistic, and publication bias was evaluated with Egger's test. A total of 23 studies were included. Lifestyle modification resulted in a significant reduction in IPFD (standardized mean difference [SMD] -0.26, 95% CI -0.36 to -0.16; p<0.0001), with low heterogeneity (I2=12.9%). The pooled absolute reduction in MRI-measured IPFD was -1.02 % (95% CI -1.30 to -0.73; p<0.0001), with no evidence of heterogeneity (I2=0%). Subgroup analyses showed the largest numerical reduction in IPFD with combined diet-and-exercise interventions (SMD -0.41, 95% CI -0.81 to -0.02, I2=29.4%), followed by exercise alone (SMD -0.26, 95% CI -0.36 to -0.15, I2=0%) and diet alone (SMD -0.22, 95% CI -0.37 to -0.08, I2=27.9%). However, differences between intervention types were not statistically significant (p=0.40). There was no evidence of publication bias (p = 0.78). Lifestyle modification is an effective non-pharmacological approach for reducing IPFD, with combined diet-and-exercise interventions showing the largest numerical effect. These findings support the potential of structured lifestyle modification programs to reduce IPFD and may have implications for the prevention and management of pancreatic diseases.

Clinical trials of interventions to preserve beta cell function in new-onset type 1 diabetes frequently employ participant-reported outcome measures (PROMs). However, the expected changes in PROMs scores immediately following diagnosis and their association with residual beta cell function, metabolic markers and continuous glucose monitoring (CGM) are unclear. Repeated PROMs including Paediatric Quality of Life Inventory diabetes module (PedsQL) and hypoglycaemia fear survey (HFS) were recorded from participants aged 10-18 years with newly diagnosed type 1 diabetes and their parents in two clinical trials: CLOuD (N=97, hybrid closed loop [HCL] vs multiple daily injections [MDI]) and USTEKID (N=72, ustekinumab immunotherapy vs placebo). Scores were compared with serial mixed meal-stimulated C-peptide levels (AUC C-peptide), HbA1c and CGM data. PedsQL and HFS scores for children/adolescents and their parents showed wide variation between individuals but did not change substantially within individuals over the first 48 months from diagnosis. Baseline scores were highly predictive of scores at 12-48 months (p<0.001). PedsQL scores were higher (better) in those reported by children/adolescents than by their parents (p<0.01). In contrast, HFS scores were higher in parents than children (p<0.001), indicating more fear. Strong correlations were observed between child and parent scores (p<0.001). No significant improvement in these scores was detected following intervention (ustekinumab or HCL). Meta-analysis revealed modest but statistically significant associations between HbA1c and PedsQL (β(std)=-0.11; 95% CI -0.20, -0.03) and HFS (β(std)=0.11; 95% CI 0.00, 0.21), and between CGM time in range and PedsQL (β(std)=0.14; 95% CI 0.03, 0.26) but not HFS (β(std)=-0.05; 95% CI -0.16, 0.06). Beta cell function (AUC C-peptide) was strongly associated with HbA1c (β(std)=-0.29; 95% CI -0.39, -0.20) and CGM time in range (β(std)=0.41; 95% CI 0.30, 0.52). Higher beta cell function showed a trend towards better PedsQL (β(std)=0.11; 95% CI -0.03, 0.25) and lower HFS (β(std)=-0.05; 95% CI -0.17, 0.07) but this did not reach statistical significance. PedsQL and HFS scores changed little during the first 48 months after diagnosis of type 1 diabetes. These scores showed modest but statistically significant associations with measures of glucose management (HbA1c and CGM time in range), whereas the relationships with residual beta cell function (C-peptide) were weaker and did not reach significance. The modest size of these effects suggests current PROMs capture only limited aspects of the clinical benefit associated with beta cell preservation. Future research should incorporate psychometric instruments that are specifically adapted for young people using modern diabetes technologies and undergoing disease-modifying therapy, to ensure outcomes are meaningfully represented in early-stage type 1 diabetes trials.

Nanoliposomal irinotecan (nal-IRI) has become an established therapy for advanced pancreatic ductal adenocarcinoma (PDAC), both in the post-gemcitabine setting and, more recently, in the first-line NALIRIFOX regimen. Concerns remain regarding cross-resistance in patients previously exposed to conventional irinotecan. We performed a systematic review and meta-analysis to evaluate the impact of prior irinotecan exposure on outcomes with nal-IRI. We conducted a systematic literature search of PubMed, Embase, and the Cochrane Library through July 2025 following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Eligible studies included patients with advanced PDAC treated with nal-IRI-containing regimens and reported outcomes stratified by prior irinotecan exposure. Data extraction and risk of bias assessments were performed independently by two reviewers. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were pooled using random-effects models. Sensitivity and publication bias analyses were conducted. Thirteen retrospective studies comprising 2271 patients were included. One-third (33.1%) had received conventional irinotecan before nal-IRI. Prior irinotecan exposure was associated with inferior outcomes: pooled unadjusted and adjusted HRs for OS were 1.48 [95% confidence interval (CI) 1.24-1.76, P = 0.001] and 1.42 (95% CI 1.03-1.96, P = 0.030), respectively. For PFS, pooled unadjusted and adjusted HRs were 1.45 (95% CI 1.28-1.64, P < 0.001) and 1.72 (95% CI 1.16-2.54, P = 0.007), respectively. Patient-level subgroup analyses indicated that patients discontinuing prior irinotecan due to progression had significantly worse OS compared with those discontinuing for other reasons (HR 1.97, 95% CI 1.10-3.52). Most studies were high quality, and sensitivity analyses confirmed the robustness of the findings. Prior exposure to conventional irinotecan, particularly discontinuation for progression, reduced clinical benefit from subsequent nal-IRI therapy in advanced PDAC in observational cohorts. These findings support caution when considering nal-IRI soon after irinotecan progression and highlight the need for prospective sequencing studies.

Mortality disparity in cancer between Black individuals and White individuals in the US has been declining since its peak in the early 1990s, but a comprehensive analysis of cancer type-specific contributions to this reduction is lacking. To examine cancer type-specific contributions to the reduction in the all-cancer excess mortality rate among Black individuals compared with White individuals between the peak period (1991-1995) and a contemporary period (2019-2023) in the US. A cross-sectional temporal analysis was conducted between March 2025 and October 2025. Non-Hispanic Black individuals and White individuals who died of cancer between 1991 and 2023 were included in the analysis. The data were compiled by the National Center for Health Statistics. Race as recorded on death certificates. All-cancer and cancer type-specific excess mortality rates per 100 000 for Black individuals compared with White individuals were calculated by sex. Changes in excess mortality rates were estimated by subtracting the current excess mortality rate for 2019 to 2023 from the peak excess mortality rate for 1991 to 1995. Cancer type-specific contributions to all-cancer excess mortality rate reduction were expressed as percentages. The analysis included 2 461 715 cancer deaths in 1991 to 1995 (11.8% non-Hispanic Black individuals; 47.4% were female) and 2 674 385 cancer deaths in 2019 to 2023 (13.2% non-Hispanic Black individuals; 47.2% were female). Between 1991 to 1995 and 2019 to 2023, the all-cancer excess mortality rate decreased by 98.4 (95% CI, 96.1-100.7) per 100 000 in Black males and by 21.7 (95% CI, 20.3-23.1) per 100 000 in Black females. Among males, lung (31.1% [95% CI, 29.9%-32.4%]), prostate (25.8% [95% CI, 24.7%-27.0%]), and esophageal (12.1% [95% CI, 11.7%-12.5%]) cancer accounted for the largest share of reductions in the all-cancer excess mortality rate. Among females, colorectal (18.8% [95% CI, 16.6%-20.9%]), cervical (16.9% [95% CI, 15.8%-18.0%]), and lung (15.1% [95% CI, 12.3%-17.9%]) cancer accounted for the largest share of reductions in the all-cancer excess mortality rate. Despite these gains in excess mortality rate reduction, prostate, lung, and stomach cancer remained among the top 5 cancer types with the largest contemporary excess mortality rate among males, whereas colorectal cancer increased in rank (from fifth to second) as well as liver cancer (from tenth to fifth), reflecting comparatively smaller or stalled progress. Breast cancer and uterine corpus cancer ranked highest during the contemporary period in excess mortality rate among Black females compared with White females (7.2 per 100 000 and 4.9 per 100 000, respectively), followed by myeloma, colorectal, and pancreatic cancer. In this cross-sectional temporal analysis, the marked reductions in excess mortality indicate meaningful progress achieved for several major cancer types through population-wide cancer control efforts. Persistent or worsening disparities in breast cancer and uterine corpus cancer and substantial residual disparities in prostate cancer highlight priorities for equitable interventions. These findings may guide more targeted and efficient cancer prevention and control strategies to further accelerate progress.

Pancreatic ductal adenocarcinoma (PDAC) arises from precursor lesions over a decade-plus, offering a window for interception in high-risk individuals, but current surveillance detects a minority of precursors. Mutant KRAS (mKRAS) is present in most PDACs and their precursors, making it an appealing target for immune-based interception. We conducted a phase I, first-in-human study of a peptide vaccine targeting six common KRAS mutations (mKRAS-VAX) in 20 individuals with hereditary PDAC predisposition and a radiographic pancreatic abnormality (NCT05013216) to assess safety, immunogenicity, and T cell persistence. Adverse events were grade 1-2. Vaccination elicited a significant mKRAS-specific T cell response in 18/20 participants (90%). Longitudinal TCR sequencing demonstrated persistence of vaccine-induced mKRAS-specific clonotypes for up to 2 years. Over a median follow-up of 16.5 months, no participants developed PDAC. These findings demonstrate that mKRAS-VAX is safe and generates durable T cell responses, which support the advancement of mKRAS-targeted vaccination for PDAC interception.

Glypican-3 (GPC3) is highly expressed in hepatocellular carcinoma (HCC), making it an attractive target for chimeric antigen receptor (CAR) T cell therapy; however, this approach has previously shown limited clinical efficacy, potentially owing to high levels of transforming growth factor-β (TGFβ) in the tumour microenvironment1-4. We therefore engineered CAR T cells with a dominant-negative TGFβ receptor II, which showed enhanced antitumour activity in preclinical studies5. Here we report findings from a first-in-human trial evaluating the safety and efficacy of C-CAR031 in patients with advanced, treatment-refractory HCC ( NCT05155189 ). Thirty-six patients received CAR T infusions at four dose levels (from 0.75 × 106 to 4.0 × 106 cells per kg). Cytokine release syndrome was reported in 34 patients, of which two cases were grade 3. Nine patients had non-haematological adverse events of grade 3 or higher. Tumour regression was observed in 32 patients, with a median best tumour reduction from baseline of 41.6% (range: 3.4-94.4%) in target lesions. The objective response rate was 44.4%, and the median duration of response was 4.4 months (95% confidence interval: 2.9-7.4). Median progression-free survival and overall survival were 4.2 months (95% confidence interval: 2.9-4.8) and 14.2 months (95% confidence interval: 10.1 to not evaluable), respectively. High-throughput analyses of tumour samples and functional validation suggested that GPC3 antigen loss and increased TGFβ levels may contribute to C-CAR031 resistance. Collectively, these results indicate that C-CAR031 has a manageable safety profile and encouraging antitumour activity in heavily pretreated patients with advanced HCC.

As the use of robotic cholecystectomy increases, its value remains poorly defined for complex elective cholecystectomy (CEC), where complex gallbladder pathology results in increased technical difficulty. To determine whether a robotic approach is associated with improved clinical outcomes and altered total hospital cost as compared with a laparoscopic approach for patients undergoing CEC. This cohort study analyzed data from an academic hepatobiliary referral center for patients who underwent cholecystectomy from August 2018 to August 2024. CEC was defined by preoperative criteria: prior aborted or partial cholecystectomy, presence of a cholecystostomy tube, and/or history of gallbladder perforation or fistula. Robotic-assisted vs laparoscopic cholecystectomy. The primary outcome was a composite of an unplanned postoperative endoscopic retrograde cholangiopancreatography or interventional radiology procedure. Secondary outcomes included operative time, postoperative complications, and operative and total hospital costs. A total of 863 patients underwent cholecystectomy and met inclusion criteria; 525 (60.8%) were female and 338 (39.2%) were male, and their median (IQR) age was 61 (45-71) years. Among patients undergoing CEC, the laparoscopic approach was independently associated with an increased need for unplanned endoscopic or percutaneous intervention compared with the robotic group (odds ratio, 4.24; 95% CI, 1.24-14.52; P = .02). There were no significant differences in postoperative outcomes between the laparoscopic and robotic groups in patients undergoing non-CEC. Patients undergoing the laparoscopic approach had significantly reduced operating room costs when compared with patients undergoing a robotic approach in both the CEC ($7720 vs $8936, respectively) and non-CEC groups ($6368 vs $ 8351, respectively). However, there was no difference in the overall total cost of care between laparoscopic CEC and robotic CEC groups ($14 309 vs $14 476, respectively). The overall total cost of care was significantly higher for patients undergoing robotic non-CEC as compared with laparoscopic non-CEC ($11 416 vs $9925, respectively). This study found that for complex gallbladder disease, robotic cholecystectomy offers a clinical advantage, reducing complications and downstream interventions without increasing the overall costs of care. These findings suggest strategic application of the robotic platform may offer clinical advantages in high-complexity gallbladder surgery, maximizing patient benefit and resource efficiency.

Despite the critical role of α-amylase assessment in diagnosing postoperative pancreatic fistula, conventional intermittent testing suffers from inherent delays, overburdened clinical laboratories, and color interference from pigmented drainage fluids. To address these limitations, we present an electrochemical biosensor enabling potential bedside continuous monitoring of α-amylase activity in abdominal drainage fluids from high-risk patients. The system integrates chronoamperometry with a glucose oxidase-functionalized cellulose fiber membrane, a carbon screen-printed electrode, and a microfluidic channel, facilitating continuous, color-immune detection in flowing clinical samples. The sensor exhibited a bilinear range of 100-10000 U/L with a detection limit of 34.7 U/L. To ensure reproducibility, single-point calibration and on-site reconstruction methods were employed to minimize batch-to-batch variability. Finally, preliminary validation using complex, dynamic-flow clinical drainage samples demonstrated reasonable agreement with hospital-reported values, indicating potential clinical utility, though larger cohort studies are warranted to fully establish accuracy and reliability. Overall, this proof-of-concept study demonstrates quantitative α-amylase detection in raw drainage fluid under dynamic flow conditions, representing a step toward continuous monitoring and clinical translation, pending further optimization.

Cancer-associated thrombosis (CAT) is a major cause of morbidity and mortality in patients with gastrointestinal (GI) malignancies and often negatively impact anti-cancer treatment delivery. A prothrombotic risk markedly varies across primary sites, from pancreatic, gastric to colorectal cancers and is influenced by tumor-driven inflammation, disease stage, and exposure to contemporary systemic therapies, including newly, immune checkpoint inhibitors, targeted agents, and antibody-drug conjugates. Despite its clinical relevance, current risk assessment models, including the pivotal Khorana score (KS), show limited accuracy in GI tumors and do not adequately account for treatment-related or biology-driven variability. This review synthesizes current evidence on the incidence, mechanisms, and clinical determinants of CAT in GI cancers and discusses approaches to primary thromboprophylaxis and secondary prevention, with attention to bleeding risk and cardiovascular considerations. Emerging strategies such as molecular profiling, inflammatory biomarkers, and ctDNA-based assessment of minimal residual disease (MRD) show promise for improving individualized risk prediction and guiding more precise anticoagulation strategies. A precision-medicine framework integrating tumor biology, dynamic biomarkers, and treatment-specific cardiovascular risk is needed to optimize CAT management and to inform future trials designed to refine primary and secondary prevention across the spectrum of GI malignancies.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy due to its aggressive biology and therapeutic resistance. Lysine-specific demethylase 1 (LSD1), an epigenetic regulator, is overexpressed in PDAC and linked to poor prognosis, yet its context-dependent roles in metabolic subtypes and chemoresistance remain undefined. Here, we show that LSD1 knockdown has opposing, subtype-specific effects on chemotherapeutic responses: it sensitized RSK-subtype cells (L3.6pl, PANC-1) to chemotherapy but induced resistance in KRAS-subtype cells (BxPC-3, TBO368). Integrated analyses revealed mitochondrial dysfunction and defective mitophagy as hallmarks distinguishing KRAS- from RSK-subtype PDAC. Critically, mitochondrial targeting through respiratory modulation or mitophagy manipulation overrides LSD1-mediated subtype-specific chemoresistance, establishing mitochondrial fitness as the mechanistic determinant. Mechanistically, LSD1 transcriptionally regulates GLS2 to drive glutamine metabolic reprogramming, promoting reductive carboxylation in KRAS-subtype cells and oxidative metabolism in RSK-subtype cells. Our work establishes the LSD1-GLS2 axis as a metabolic switch controlling PDAC chemosensitivity and provides a framework for subtype-specific therapeutic strategies.

Ultrasound-induced luminescence offers a light-free imaging modality with deep tissue penetration and spatiotemporal controllability; however, its broader application is hindered by weak luminescent signals that limit imaging depth and signal-to-noise ratios. Here, we report an organic-inorganic heterojunction sonosensitizer, TA@TiO2, formed by coupling a trianthracene derivative (TA) with titanium oxide (TiO2). Under ultrasound irradiation, the nanoscale charge-transfer interface promotes interfacial charge transfer, significantly enhancing reactive oxygen species (ROS) generation. This increased ROS triggers amplified chemical energy conversion, resulting in a markedly enhanced ultrasound-induced luminescence signal for deep-tissue optical imaging. Compared to TA nanoparticles, TA@TiO2 exhibits superior signal transmission in scattering media and maintains high luminescence at lower power densities. In vivo studies demonstrate that TA@TiO2 enables high-contrast imaging of deep-seated tumors, such as pancreatic cancer and glioma, while providing enhanced sonodynamic therapy efficacy. The positive correlation between ultrasound-induced luminescence intensity and ROS generation allows for dynamic, imaging-guided tumor therapy. These results establish heterojunction engineering as a potent strategy for advancing ultrasound-activated theranostics.

Our goal is to develop RNA-guided engineering of the chloroplast genome using the CRISPR/Cas9 system. We designed chloroplast minigenes to obtain properly sized single guide RNAs (sgRNAs) in tobacco chloroplasts. The sgRNA 5' end is defined by transcription from an rRNA operon promoter, and its 3' end by processing a downstream tRNA (trnG) or a hepatitis delta virus (HDV) ribozyme. Cas9 is expressed from a nuclear gene and is targeted to chloroplasts by fusion to a transit peptide. Cas9 incorporated the sgRNA and introduced double-strand breaks in the plastid DNA (ptDNA). We report here that the double-strand DNA break in the ndhA and rpoC1 genes was repaired by microhomology-mediated end joining (MMEJ), resulting in deletions in the ptDNA. We further showed that nuclear-expressed sgRNA can be delivered into chloroplasts by fusion with a viroid RNA, as one possible approach for RNA-guided engineering of the ptDNA without direct chloroplast genome transformation. These results are the first step of RNA-guided editing of the chloroplast genome in any crop.

Pancreatic cancer (PC) remains a highly lethal malignancy presenting formidable therapeutic challenges, primarily attributable to the substantial barriers posed by its dense desmoplastic stroma, profoundly immunosuppressive microenvironment, and poor drug bioavailability. Nanotechnology offers an effective strategy to enhance therapeutic efficacy through improved targeting, optimized pharmacokinetics, enhanced tissue penetration, increased biosafety, and high clinical translational potential. Consequently, this nanotechnology-based platform has been extensively investigated over the past decade for treating PC. This review examines a comprehensive overview of nanoparticle-mediated delivery systems for targeted PC therapy, critically evaluating recent developments and ongoing hurdles along the bench-to-bedside pathway. We discuss applications across chemotherapy, immunotherapy, gene therapy, and other modalities employed as monotherapies or combination regimens.

Pancreatic ductal adenocarcinoma (PDA) is an aggressive cancer that frequently presents with disseminated disease. The PDA metastatic microenvironment imposes distinct metabolic stressors, potentially generating context-dependent vulnerabilities. Therefore, we employed CRISPR-based genetic screening in a model of PDA liver metastasis to identify novel and possibly targetable liabilities. Remarkably, ferritin heavy chain (FTH1) emerged as the most prominent liver-specific dependency - loss of FTH1 suppressed tumor growth specifically in the liver microenvironment. FTH1 deletion and subsequent disruption of iron handling triggers mitochondrial dysfunction and ionic imbalance, including cytosolic calcium overload. These perturbations result in the activation of a transcriptional program that triggers anti-tumor immunity mediated by immunostimulatory cytokine IL36G. Mechanistically, FTH1 deletion and subsequent ionic imbalance causes decreased protein levels of the tumor suppressor Stk11 (LKB1) which we propose to be mediated by an RNA G-quadruplex located in the 5'-UTR of LKB1. The loss of LKB1 protein levels alters signaling cascades resulting in reduced SIK signaling and inhibition of nonsense mediated decay, ultimately leading to Il36g mRNA stabilization. Taken together, this work elucidates novel ionic disruptions that regulate the translation of LKB1 through a previously undescribed quadruplex in the 5'UTR, altering signaling axes that can be targeted to generate an anti-tumor immune response in PDA.

Pancreatic islets respond to obesity-related insulin resistance by increasing β cell mass and insulin secretion. However, the molecular mechanisms behind this vital compensation are not fully understood. This study shows that adaptive islet-derived small extracellular vesicles (aid-sEVs) play a key role in β cell adaptation in obesity. Aid-sEV production rises under hyperlipidemic conditions, and uptake by adjacent cells occurs via F11R-mediated recognition. Mesenchymal stem cells (MSCs) act as downstream effectors after they internalize aid-sEVs, promoting β cell-adaptive responses. These vesicles deliver miR-151 to MSCs, triggering miR-151-dependent cellular reprogramming toward a Wnt-secreting phenotype. Restoration of miR-151 in microRNA-deficient aid-sEVs restores their proadaptive effects on β cells. Klf9, a direct target of miR-151, is involved in regulating MSC proliferation and WNT secretion by controlling Wnt3a and Ccnd1 transcription. These findings reveal a critical pathway controlling β cell compensation in diet-induced obesity and indicate that targeted enhancement of aid-sEV secretion could be a therapeutic strategy to counteract β cell dysfunction in diabetic patients.

Therapeutic resistance remains a prevalent and intractable clinical challenge across a broad spectrum of human malignancies. Despite extensive investigations, the intricate molecular networks by which the tumor microenvironment (TME) mediates such resistance are not fully understood. In this study, we identified nucleotide-binding oligomerization domain-containing proteins 1 and 2 (NOD1/2) as pivotal regulators of adaptive resistance to diverse antitumor therapies, including immune checkpoint blockade (ICB), adoptive T-cell therapy, and cytotoxic chemotherapy. In murine tumor models, genetic ablation of NOD1/2 or receptor-interacting protein kinase 2 (RIPK2), as well as pharmacological inhibition of RIPK2, remodeled the TME by decreasing immunosuppressive macrophages and boosting CD8⁺ T cell infiltration and cytotoxicity. Mechanistically, NOD1/2 activation in macrophages upregulated programmed death-ligand 1 (PD-L1) expression via the RIPK2/NF-κB signaling axis, establishing an immunosuppressive TME that impaired CD8⁺ T cell-mediated antitumor immunity. Notably, in the clinically relevant setting of immunotherapy resistance, targeted suppression of NOD1/2 signaling in patient-derived peripheral blood mononuclear cells (PBMCs) restored and potentiated ICB responsiveness in patient-derived tumor organoids. Bioinformatic analyses further demonstrated that NOD1/2-associated gene signatures were significantly enriched in tumor-associated macrophages post-therapy. Our findings define NOD1/2 as a novel innate immune checkpoint that orchestrates therapy-induced adaptive resistance and highlight this pathway as a promising target to overcome treatment resistance in refractory cancers.

Osteogenesis imperfecta (OI) is a rare bone fragility disorder. Previously, in a severe OI mouse model (Col1a1Jrt/+), a sex- and age-dependent metabolic phenotype was observed, correlating with elevated levels of the bone-derived hormone osteocalcin (OCN). This hormone is known to play a crucial role in managing energy metabolism, including glucose regulation and fat mass. In fact, upon high-fat diet (HFD) exposure, OI mice developed a metabolic syndrome linked to sex and OCN. To assess OCN's role in OI, Col1a1Jrt/+ mice were crossed with OCN-deficient mice (Bglap). Under regular chow and HFD conditions, both OCN-dependent and OCN-independent metabolic alterations were identified. OCN-dependent processes were adipose tissue, liver, and insulin metabolism in a sex-, age-, and diet-dependent manner. OCN-independent traits included the pancreas in juvenile mice, HFD-induced pancreatic insulin levels and glucose intolerance, besides overall growth, fertility, and bone phenotype. Notably, increased juvenile energy expenditure was OCN-independent, while HFD-induced changes were OCN-driven. These findings demonstrate OCN's role in shaping the metabolic phenotype while revealing distinct OCN-independent effects, emphasizing the complex genetic regulation of metabolism in OI.

For decades, we have viewed pancreatic fibrosis as a passive scar-the end-stage wreckage of chronic inflammation or a late accomplice of growing tumors. A recent study by He Ren and colleagues sheds critical light on the origins of the phenomenon tracing it to an unexpected cellular culprit: a rare subset of pancreatic epithelial cells that express FOXP3-a transcription factor predominantly associated with regulatory T cells. These epithelial FOXP3 (E-FOXP3) positive cells do not need oncogenic Kras or overt inflammation to ignite fibrosis. On their own, they orchestrate a glycosylation-dependent IL-6 switch that turns quiescent pancreatic stellate cells into a self-amplifying fibrotic machine. In discovering a proto-fibrogenic "trigger cell" that acts silently, long before any symptom or radiological sign, the work redefines the cellular hierarchy of pancreatic fibrocarcinogenesis. Further, the paper identifies a post-translational "sugar code" as a therapeutic foothold, and opens a long-sought preemptive window for intercepting pancreatic cancer at its most curable stage-before the desmoplastic fortress is ever built.

The biological significance of forkhead box A1 (FOXA1) in non-steroid-driven malignancies, such as pancreatic ductal adenocarcinoma (PDAC), has garnered increasing recognition. It assumes a pivotal role in regulating critical processes such as PDAC cell lineage, metabolism, and metastasis. However, its regulatory mechanisms remain elusive. Here, we demonstrate that histone deacetylase 5 (HDAC5) mediates the deacetylation of FOXA1 at lysine residue 270 (K270), leading to repression of FOXA1's global chromatin occupancy. In HDAC5-loss PDAC, K270 hyper-acetylated FOXA1 is reprogrammed to the transcription start sites (TSSs) of HIF1α-targeted genes, functioning as a pioneer factor of HIF1α signaling. Additionally, we show that HDAC5 antagonizes LSD1-mediated FOXA1 activation by converging on the dynamic equilibrium of acetylation-methylation transition at K270. Pharmacological inhibition of HIF1α/LSD1 suppresses the growth and progression of HDAC5-deficient PDAC in in vivo and in vitro models. Our study reveals the role of FOXA1 as a pioneer factor of HIF1α in PDAC, providing potential therapeutic strategies for HDAC5-deficient PDAC.

Plastic substrates are ubiquitously colonized by complex microbiomes, referred to as the plastisphere. Diatoms, despite being considered the main autotrophic taxa and key early colonizers involved in biofilms, currently remain poorly studied compared to other microbes plastic pieces were immersed in coastal systems at six locations across five countries in the Atlantic Ocean and the Mediterranean Sea. Spatial and seasonal dynamics of plastic-attached diatom communities were investigated by incubating polyethylene (HDPE) at all sites for 84 days. Temporal dynamics at each season were also investigated using HDPE, polypropylene, and polystyrene in Toulon only (North-Western Mediterranean Sea). Using amplicon sequencing of the rbcL gene, geographic location appears to be the primary driver of diatom diversity, followed by season and incubation time, with intra-site variations always smaller than those between sites. Intra-site variations were mostly due to relative abundance changes, while inter-site variations corresponded to shifts between species. Biofilms from the Atlantic shared neither species nor ASVs, whereas biofilms from the Mediterranean shared 5 species and 5% of reads. Pioneer taxa changed depending on the season, while mature taxa tended to converge irrespective of the season. Finally, the nature of conventional plastics plays a minor role in shaping the diatom community, as shown previously for heterotrophs in the plastisphere. Overall, the shaping of diatom communities in biofilms could be observed at different taxonomic levels, down to the genetic variant, highlighting the extent to which genetic divergence occurs. Finally, potential ecological consequences of diatom presence and diversity in the plastisphere are discussed.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers due to its aggressive biology and resistance to existing therapies. Oncofetal chondroitin sulfate (ofCS) is a tumour-restricted glycosaminoglycan broadly expressed across solid cancers but largely absent from normal adult tissues. We developed C9-based chimeric antigen receptor (CAR)-T cells targeting ofCS to overcome poor antigen specificity and the immunosuppressive tumour microenvironment (TME). To optimise ofCS-targeted C9 CAR-T cell therapy for PDAC through integrated CAR design optimisation, metabolic enhancement and TME reprogramming. C9 and charge-optimised C9-66 CAR-T cells were engineered using a humanised ofCS-binding single-chain antibody fragment. Antitumour efficacy, functional durability and metabolic fitness were assessed in murine and patient-derived PDAC models. Enhancement strategies included inosine-mediated metabolic reprogramming, Nr5a2 overexpression and sequential TME remodelling using GLP-1R modulation, CSF-1R blockade and programmed cell death protein-1 inhibition. C9 CAR-T cells exhibited potent cytotoxicity, delayed tumour progression and extended survival in PDAC models. Compared with the parental construct, charge-optimised C9-66 CAR-T cells showed reduced exhaustion and more sustained activity in vivo. Inosine enhanced cytokine production, promoted central-memory differentiation and mitigated exhaustion, whereas Nr5a2 overexpression increased mitochondrial respiration and cytotoxicity. Sequential GLP-1R on-off modulation with macrophage and checkpoint blockade enhanced intratumoural CAR-T cell activity and prolonged survival. Human C9-66 CAR-T cells retained specific ofCS recognition and lysed patient-derived PDAC cells in vitro and in vivo. C9-66 CAR-T cells with metabolic optimisation and TME reprogramming represent a tumour-specific and clinically translatable immunotherapeutic strategy for PDAC and other ofCS-expressing solid tumours.

Gemcitabine remains a cornerstone treatment for pancreatic ductal adenocarcinoma (PDAC), yet the emergence of resistance constitutes a major clinical challenge with poorly understood epigenomic mechanisms. Here, we identified the pioneer transcription factor Foxa1 as a master regulator of gemcitabine resistance through multi-omics analysis. Mechanistically, Foxa1 drives widespread super-enhancer (SE) reprogramming and 3D genome remodelling in resistant cells, which coordinately activates the expression of key resistance genes, notably Rrm1 and Cdadc1. This is accompanied by increased chromatin accessibility, elevated H3K27ac enrichment at SEs, and enhanced Foxa1 binding at regulatory elements. Moreover, post-translational stabilization of Foxa1 via USP7-mediated deubiquitination sustains this epigenomic program. Genetic ablation of Foxa1 or specific SE regions near Rrm1 resensitizes resistant cells to gemcitabine. Building upon this mechanism, we demonstrate that bromodomain and extraterminal (BET) inhibitors, which disrupt SE function, potently reverse resistance. Notably, the clinical-stage BET inhibitor AZD5153, in combination with gemcitabine, achieves robust tumor suppression and overcomes resistance in cell-derived xenograft (CDX) models by dismantling the Foxa1-mediated resistant transcriptome and reinvigorating drug sensitivity. Our findings establish Foxa1-orchestrated enhancer reprogramming as a fundamental mechanism of gemcitabine resistance and unveil a promising epigenetic therapy to restore treatment efficacy in PDAC.

The vagus nerve regulates inflammation via sensory-motor arcs. While vagal sensory neurons relay signals from within the body (interoception), whether external inputs can regulate visceral neuroimmune responses (exteroception) remains poorly understood. We unveiled a skin-lung reflex by which sensory neurons from the auricular skin suppressed Alternaria alternata-induced allergic airway inflammation. Viral and chemical neural tracing revealed distinct sensory projections from the vagal ganglia to the auricular skin. Pharmacologic, chemogenetic, and optogenetic activation of auricular transient receptor potential vanilloid 1 (TRPV1)+ afferents attenuated type 2 allergic lung inflammation, including group 2 innate lymphoid cell, eosinophil, and type 2 cytokine responses in the airway. Conversely, silencing of these sensory neurons via the skin exacerbated lung inflammation, and immunosuppression of airway inflammation was dependent on the neuropeptide calcitonin gene-related peptide (CGRP)β. These findings reveal an evolutionarily conserved somato-visceral reflex by which exteroceptive inputs impact visceral inflammation. Thus, transcutaneous neuromodulation may represent a therapeutic strategy to treat visceral inflammation.

T-cell exhaustion in the tumor microenvironment undermines antitumor immunity and limits immunotherapy efficacy. Further defining the metabolic triggers of this dysfunctional state could provide therapeutic targets for circumventing immunosuppression. In this study, we identified soluble uric acid (UA)-an abundant purine metabolite frequently elevated in patients with cancer-as a metabolic checkpoint that drives the exhaustion of CD8+ T cells and immune evasion in colorectal cancer. In hyperuricemic mouse models, elevated UA accelerated tumor progression in immunocompetent hosts, but not in T cell-deficient ones, by functionally exhausting tumor-infiltrating CD8+ T cells. Mechanistically, UA directly bound the kinase scaffold kinase suppressor of Ras 1 (KSR1) and hyperactivated MEK-ERK signaling, leading to chronic MAPK stimulation that upregulated inhibitory receptors, including PD-1 and Tim-3, on CD8+ T cells and blunted their cytotoxic function. Genetic disruption of this UA-KSR1-MAPK axis via Tim-3 knockout or Ksr1 knockdown restored T-cell effector activity and tumor control. Notably, pharmacologic UA depletion with the clinical xanthine oxidase inhibitor febuxostat reinvigorated CD8+ T cells, slowing tumor growth and markedly enhancing the efficacy of both chemotherapy and adoptive T-cell therapy in vivo. These findings establish soluble UA as a metabolic immune checkpoint that subverts antitumor T-cell immunity. Targeting UA metabolism may offer a strategy to overcome immune resistance and improve the efficacy of cancer immunotherapies. A common metabolic byproduct, soluble uric acid, can act as an immune checkpoint that drives T-cell exhaustion, redefining how systemic metabolism shapes cancer progression.

This study developed a novel ternary solid dispersion premix by dispersing phloretin-trilobatin co-amorphous mixture (1:2 M ratio) into erythritol via solvent evaporation to simultaneously enhance solubility and glycolipid-regulating bioactivity. The formulation markedly improved aqueous solubility, achieving >28-fold and > 15-fold increases for phloretin and trilobatin, respectively. Comprehensive characterization through powder X-ray diffraction, differential scanning calorimetry, Fourier-transform infrared spectroscopy, and scanning electron microscopy, combined with density functional theory and molecular dynamic simulations, verified a homogeneous amorphous structure stabilized by hydrogen bonding and hydrophobic interactions. In vitro evaluation demonstrated dual inhibition of pancreatic lipase and cholesterol esterase, synergistic suppression of α-glucosidase, and delayed starch digestion. Network pharmacology and molecular docking identified multi-target modulation of glycolipid metabolism via pathways including PI3K/AKT and MMP9. This food-grade, scalable approach offers a promising strategy for sugar-reduced functional ingredients, integrating solubility enhancement with metabolic benefits for managing hyperglycemia and hyperlipidemia in functional foods and beverages.

High-pressure processing (HPP) is a promising non-thermal technology for enhancing the bioactivity of polyphenolic compounds. This study investigated the impact of varying HPP conditions (100-600 MPa, 2-10 min) on the antioxidant capacity, resveratrol content, and inhibitory effects against α-glucosidase, cholesterol esterase, and pancreatic lipase. Resveratrol treated with 200-300 MPa for 2 min exhibited significantly higher antioxidant activities (DPPH, ABTS, FRAP, CUPRAC, and DMPD) and enzyme inhibition effects, correlating with increased resveratrol content. Principal component analysis and heatmap visualisation confirmed a strong association between antioxidant performance and enzyme inhibition. These findings suggest that moderate HPP enhances the functional properties of resveratrol, offering a feasible strategy for developing functional foods targeting metabolic disorders. However, further in vivo validation and mechanistic studies are warranted. This study highlights HPP's potential as a clean-label approach to optimising the health benefits of dietary polyphenols.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by frequent KRAS mutations, which activate the MAPK pathway to promote PDAC progression. In this study, we explored metabolic vulnerabilities of PDAC by assessing initial metabolic reprogramming upon ERK inhibition using metabolomics, lipidomics, and isotope-tracing experiments. ERK inhibition enhanced lipid turnover and fatty acid (FA) oxidation while inhibiting glycolysis, glucose oxidation, and glutamine metabolism in PDAC cells. Moreover, lipophagy, but not cytosolic lipolysis, was responsible for the increased lipid turnover and FA oxidation upon ERK inhibition. Lipophagy and lipophagy-fueled FA oxidation were induced by increased nuclear translocation and activity of the transcription factor TFEB. Pharmacologic inhibition of FA oxidation in combination with KRASG12D/MEK/ERK inhibitors synergistically decreased the growth of PDAC cell lines and organoids. The combination decreased tumor burden and improved survival in orthotopic cell line and patient-derived xenograft PDAC models. Overall, this study provides mechanistic insights into the development of metabolic resistance to KRAS signaling inhibition and demonstrates that FA oxidation is a metabolic vulnerability following KRAS signaling inhibition that can be utilized as an effective therapeutic target to treat PDAC. Treating pancreatic cancer with inhibitors that target the KRAS pathway rewires metabolism by increasing lipophagy and fatty acid oxidation, which can be targeted to sensitize tumors to KRAS signaling inhibition. See related commentary by Delgado Herrera and Ferrer, p. 3374.

KRAS mutations are among the most prevalent oncogenic alterations in colorectal, lung and pancreatic cancer, yet their detection remains analytically challenging in the presence of an overwhelming wild-type (WT) background. Here, we report a photoelectrochemical (PEC) genotyping platform that integrates clamp-inhibited loop-mediated isothermal amplification (C-LAMP) with enzyme-free singlet oxygen (1O2)-driven PEC transduction for mutation-selective KRAS detection. Locked nucleic acid (LNA) clamp probes selectively suppress WT amplification during isothermal amplification, enriching mutant alleles and enabling single-nucleotide variant (SNV) discrimination with high selectivity. Amplified products are magnetically captured and transduced into photocurrent via visible-light-induced 1O2 redox cycling, eliminating enzymatic reporters and reducing background interference. The C-LAMP/PEC platform achieves a limit of detection of 35 copies μL-1 (58 aM) and a minimum detectable variant allele frequency (VAF) of 4.8% in heterogeneous mutant/WT genomic DNA mixtures. Analytical performance was validated in cancer cell lines and in patient-derived fresh frozen tissues, showing complete concordance with Nanopore sequencing and droplet digital PCR (ddPCR) within the evaluated cohort (n = 16). This work introduces a robust and modular PEC biosensing strategy that combines molecular WT suppression with enzyme-free photoelectrochemistry, offering an economically competitive and instrumentation-simplified approach for clinically relevant KRAS mutation analysis toward decentralized testing.

Multiple organ dysfunction syndrome presents a significant challenge in clinical critical care, characterized by the progressive or simultaneous failure of two or more organ systems following severe insults such as infection, trauma, acute pancreatitis, shock, burns, or other major events. Recent advancements in research have deepened the understanding of organ dysfunction, with a shift toward investigating organ injury and organ-specific diseases. The pathogenesis of MODS is intricate and driven by dynamic interactions across multiple levels, including inflammatory responses, microcirculatory disruptions, coagulation abnormalities, cell death, DNA damage and the production of reactive oxygen species. Recent innovations in single-cell technologies, spatial omics and organoid models have opened new avenues for exploring intercellular signaling, targeting damaged tissues and advancing drug development. Current therapeutic approaches for MODS involve comprehensive strategies, such as aggressive management of underlying causes, organ support, modulation of immune and inflammatory responses, nutritional intervention and stabilization of the internal environment. Despite these efforts, mortality rates remain high, and therapeutic advancements have yet to yield optimal results. This highlights the urgent need for continued research to translate scientific discoveries into clinical breakthroughs. Further exploration of the disease's pathogenesis, identification of early diagnostic biomarkers and development of novel, effective treatments are crucial to improving treatment outcomes and reducing mortality in critically ill patients.

In cancer cells, pyruvate generated through aerobic glycolysis is preferentially converted into lactate. Here, we examined the impact of aerobic glycolysis on innate immune regulation within the tumor microenvironment. We identified lactate as a potent suppressor of stimulator of interferon genes (STING)-mediated innate immune signaling. Lactate directly bound the cyclic GMP-AMP (cGAMP)-binding domain of STING, thereby inhibiting cGAMP binding, STING activation, and interferon regulatory factor 3 (IRF3)-dependent cytokine expression. Mechanistically, activation of epidermal growth factor receptor (EGFR) promoted phosphorylation of lactate dehydrogenase A (LDHA) by pyruvate kinase M2 (PKM2) at serine 161 (S161). This increased LDHA activity and lactate production, which suppressed immune cell infiltration and promoted tumor growth. Pharmacological PKM2 inhibition relieved lactate-mediated STING suppression, reduced tumor immune evasion, and synergized with anti-PD-1 therapy. In human glioblastoma, elevated LDHA S161 phosphorylation correlated with reduced STING activation, diminished cytotoxic immune cell infiltration, and poor survival. Thus, oncogenic signaling directs PKM2-generated pyruvate toward LDHA-mediated lactate production, which directly inhibits STING to silence innate immune activation.

Bisphenol F (BPF) is a common substitute for bisphenol A and the most prevalent bisphenol compound in diverse plastic manufacturing applications. However, the potential toxicity of BPF remains largely unexplored. This study investigates the effects of BPF on the cardiovascular system and intestinal barrier. Germ-free mouse models and fecal microbiota transplantation techniques were used to confirm the role of gut microbiota in BPF-induced cardiovascular injury. Untargeted metabolomics and spatial metabolomics were used to identify the in vivo metabolic products of BPF. Single-cell sequencing was used to identify which cardiac cell types were damaged by BPF exposure. BPF was detected in 90.5% of 285 human urine samples (median, 1.16 ng/μg creatinine). BPF exposure induced cardiomyocyte hypertrophy, cardiac dysfunction, and intestinal barrier damage, effects contingent on the presence of gut microbiota. Metabolomic analysis identified the microbial conversion of BPF to N-acetylputrescine (NAP). Mechanistically, we found that BPF stimulated intestinal epithelial cells to secrete spermidine/spermine N1-acetyltransferase 1 (Sat1), which catalyzed this conversion. Furthermore, NAP impaired the intestinal barrier by disrupting the Golgi-mitochondria axis and caused cardiac hypertrophy by activating the p53 pathway and inhibiting glycolysis in cardiomyocytes. Supplementation with Akkermansia muciniphila or its metabolite tryptophol mitigated BPF-induced cardiac and intestinal injuries by downregulating the Sat1-NAP axis. Clinical analysis further showed elevated serum NAP levels in patients with inflammatory bowel disease, positively correlating with cardiac injury markers. BPF disrupts intestinal barrier function through microbial metabolism involving the tryptophol/Sat1 pathway, leading to NAP production. NAP damages intestinal organelles and enters circulation, inducing cardiac p53 activation and hypertrophy. This study delineates a novel gut microbiota-Sat1-NAP pathway underlying BPF-induced cardiotoxicity, offering new insights for risk assessment and therapeutic intervention.