Acute pancreatitis (AP) is a severe inflammatory disorder with limited therapeutic options. Novel bile acids have emerged as potent immunomodulators, but the function of norcholic acid (NorCA) previously remained unknown. In this study, we identified NorCA’s role as a novel immunomodulator that alleviates acute pancreatitis through peroxisome proliferator-activated receptor α (PPARα)-mediated macrophage reprogramming and efferocytosis. Targeted metabolomics was performed on serum from patients with AP and caerulein-induced AP mice. The functional role and mechanism of NorCA were investigated using flow cytometry, immunofluorescence, efferocytosis assays, and network pharmacology, both in vitro and in vivo. Our findings indicate that NorCA levels were significantly elevated in both patients and mice with AP, correlating with disease severity and complications. NorCA treatment markedly reduced serum amylase/lipase and pancreatic histopathological damage in AP mice. Mechanistically, NorCA promoted M1-to-M2 macrophage reprogramming and enhanced efferocytosis of apoptotic cells. These effects were dependent on PPARα activation, as demonstrated by siRNA silencing and pharmacological antagonism. These findings position NorCA as a promising therapeutic candidate and severity-associated metabolite in AP.

Radiation-induced intestinal injury (RIII) remains a major clinical challenge, partly due to the lack of local delivery systems capable of concurrently coordinating oxidative stress and immune responses at the lesion site. In this study, we identify the transmembrane mucin MUC13 as a key regulator of intestinal epithelial homeostasis. MUC13 deficiency aggravates oxidative stress, epithelial apoptosis, and inflammatory responses, whereas supplementation with recombinant human MUC13 (rhMUC13) markedly attenuates epithelial injury. To achieve site-specific and durable delivery to inflamed tissue, we developed an inflammation-responsive polydopamine-gelatin methacryloyl (PDA-GelMA) hydrogel microsphere system that integrates targeted local delivery with intrinsic microenvironment modulation. The therapeutic efficacy arises from complementary, component-specific functions. The PDA shell mediates inflammation-associated adhesion and prolonged mucosal retention, rapidly scavenges reactive oxygen species (ROS), suppresses early inflammatory amplification, and promotes macrophage polarization toward a reparative M2 phenotype. Within this favorable redox-immune milieu, the GelMA core enables sustained rhMUC13 release, enhancing epithelial survival and barrier reconstruction by inhibiting NF-κB-associated pro-apoptotic signaling (the Bax/Bcl-2 axis) and restoring tight-junction proteins (ZO-1, Occludin, and Claudin-1). This cooperative mechanism likely accounts for the superior efficacy of the composite microspheres compared with single-component controls. Moreover, 16S rRNA gene sequencing revealed that irradiation induces pronounced gut microbiota dysbiosis, characterized by disrupted microbial diversity and community structure, increased inflammation-associated opportunistic taxa, and reduced beneficial commensal/metabolism-related bacteria; notably, PDA-GelMA@rhMUC13 partially ameliorated irradiation-induced dysbiosis, showing an overall remodeling trend toward reduced inflammation-associated taxa and increased putatively beneficial and metabolism-related bacteria. Collectively, these findings establish MUC13 as a critical mediator of epithelial-immune crosstalk and introduce a multifunctional hydrogel microsphere platform that combines targeted protein delivery with endogenous antioxidative and immunomodulatory capacities. This strategy may additionally promote restoration of intestinal homeostasis through microbiota remodeling, offering translational potential for RIII and other inflammatory intestinal disorders.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis, particularly in the presence of liver metastases. The mechanisms by which metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), influences PDAC progression and metastasis remain poorly understood. This study investigates the role of MASLD in fostering an immunosuppressive microenvironment conducive to PDAC liver metastases and identifies the macrophage migration inhibitory factor (MIF)-CD44 axis as a key mediator of this process. Utilizing data from the UK Biobank (450,754 participants, median follow-up 14.5 years), we observed an overall increased risk of PDAC in the MASLD population (HR: 3.48; 95% CI: 2.69–4.50; P < 0.0001). Clinical cohorts confirmed the strong association between MASLD and hepatic metastases (OR: 7.06; 95% CI: 4.62–10.78; P < 0.0001). Experimental mouse models demonstrated that MASLD enhances tumor cell stemness, immune evasion, and focal adhesion in metastatic liver tissues. Mechanistically, MASLD-induced MIF secretion promotes CD44-positive PDAC cell migration, stemness, and adhesion. Targeting MIF, either genetically or pharmacologically using the MIF tautomerase inhibitor IPG1576 significantly attenuated liver metastasis in preclinical models. Validation in patient samples revealed elevated hepatic MIF and CD44 expression in MASLD-associated PDAC liver metastases. This study highlights the MIF-CD44 axis as a promising therapeutic target and underscores the importance of tailoring treatments for PDAC patients with concurrent MASLD.

Background This study aimed to compare the performance of two advanced large language models (LLMs), DeepSeek-R1 and ChatGPT-o1, in addressing health law-related questions from the Chinese National Medical Licensing Examination (CNMLE), thereby evaluating their applicability in medical education in non-English contexts. Methods A total of 400 health law questions were randomly selected from the official CNMLE guidebook. Each question was independently administered to DeepSeek-R1 and ChatGPT-o1 via standardized Application Programming Interfaces (API) prompts to minimize hallucination and memory effects. Model responses were compared against the official answers, and statistical analyses were conducted using McNemar's test, with p < 0.05 indicating significance. Results DeepSeek-R1 achieved an overall accuracy of 93.5% (374/400), significantly higher than ChatGPT-o1's 79.5% (318/400, p < 0.001). Subgroup analysis revealed that DeepSeek-R1 consistently outperformed ChatGPT-o1 across most legal categories, including medical institutions, infectious disease prevention, malpractice liability, and pharmaceutical regulation. Both models performed comparably in categories such as blood donation and maternal-child health law. DeepSeek-R1 also achieved perfect accuracy in smaller domains such as public health emergencies and occupational disease control. Conclusion DeepSeek-R1 demonstrated superior performance compared with ChatGPT-o1 in answering health law questions within the CNMLE, highlighting its potential as a reliable tool for medical education in China. The findings underscore the influence of linguistic and cultural context on LLM performance. Future work should expand evaluation to open-ended and case-based questions and explore fine-tuning strategies to enhance the accuracy in healthcare settings.

The liver and pancreas are metabolically intertwined organs whose bidirectional communication is critical for maintaining systemic homeostasis. Dysregulation of this inter-organ crosstalk is a central driver in the pathology of a growing list of prevalent diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), liver cancer, acute and chronic pancreatitis, and various forms of diabetes. Given the substantial global health burden of these conditions and the lack of effective, Food and Drug Administration (FDA)-approved pharmacological interventions for those diseases, understanding the intricate mechanisms is an urgent and timely endeavor. This review provides a comprehensive synthesis of recent advancements in deciphering the molecular basis of liver-pancreas communication. We explore the multifaceted signaling networks involved, including the roles of liver-derived hepatokines, pancreas-derived hormones, extracellular vesicles, and metabolic exchanges. This axis is further integrated within broader systemic networks involving the gut, neuronal system, adipose tissue, and skeletal muscle. While clinical trials targeting this communication show promise (e.g., FGF21- and bile acid-related drugs), significant challenges remain, particularly the lack of FDA-approved pharmacological treatments for alcohol-associated liver disease (ALD), and acute/chronic pancreatitis. Future research must elucidate specific signaling pathways, identify novel pancreas-derived factors, and develop innovative therapeutic strategies. In particular, small molecule drug discovery based on polypharmacology, for these complex metabolic and organ-specific diseases.

Objectives This study investigated the protective effects and mechanisms of rhaponticin (Rha) against acinar cell injury in acute pancreatitis (AP).Methods Pancreatic acinar cell injury was induced using multiple in vitro and in vivo AP models. The mitochondrial function, necrosis, and oxidative stress were assessed. Network pharmacology and molecular docking were applied to predict potential molecular targets, which were subsequently validated experimentally. The involvement of hypoxia-inducible factor 1-alpha (HIF-1α) signaling and necroptosis-related proteins, including receptor-interacting protein kinase 3 (RIP3) and phosphorylated mixed lineage kinase domain-like protein (p-MLKL), was further explored. Both pharmacological inhibition and siRNA-mediated knockdown were employed to verify the target specificity of Rha.Results Rha treatment significantly preserved mitochondrial function, reduced ROS, and alleviated pancreatic injury. Network pharmacology and molecular dockingresults identified HIF -1a as the key target of Rha. Consistently, Rha treatment markedly downregulated HIF-1α expression and inhibited necroptosis by suppressing the activation of RIP3 and p-MLKL. Notably, neither pharmacological inhibition nor siRNA-mediated knockdown of HIF-1α produced additional protective effects in the presence of Rha, indicating the involvement of HIF-1α in mediating its actions.Conclusion Rha effectively attenuates acinar cell necrosis and oxidative via the HIF-1α-mediated necroptosis pathway, highlighting Rha as a promising therapeutic candidate for AP.

Intra-abdominal hypertension (IAH) is a life-threatening condition associated with increased morbidity and mortality in intensive care unit (ICU) patients. Autonomic nervous system dysfunction, reflected by altered heart rate variability (HRV), has shown prognostic significance in critical illness. This study aimed to evaluate the prognostic value of HRV in predicting mortality among IAH patients. In the Medical Information Mart for Intensive Care III (MIMIC-III) database, we retrospectively identified adult ICU patients who had both intra-abdominal pressure (IAP) measurements and electrocardiogram (ECG) recordings available. According to IAP measurements, patients were divided into a normal IAP (N-IAP) group and an IAH group. Twelve HRV parameters were derived from RR intervals. A multivariable logistic regression model including both Sequential Organ Failure Assessment (SOFA) score and HRV variables was developed to predict in-hospital mortality. Model performance was evaluated using receiver operating characteristic (ROC) curves and area under the curve (AUC), and was compared with a SOFA-only model. Internal validation was performed using bootstrap resampling. Among 202 patients, HRV was significantly lower in the IAH group than in the N-IAP group. Deceased IAH patients exhibited significantly lower HRV than survivors. The combined SOFA and HRV model achieved an AUC of 0.832 for predicting in-hospital mortality, which was higher than that of the SOFA-only model (AUC = 0.801). Diminished HRV is a critical prognostic marker for mortality in patients with IAH. Incorporating HRV into the SOFA-based model improves predictive performance for in-hospital mortality compared with the SOFA score alone.

Intrapancreatic fat deposition (IPFD) has garnered appreciable attention across diverse medical disciplines amid the rising global burden of pancreatitis, pancreatic cancer and type 2 diabetes mellitus. Despite growing interest in the field, there remains no conceptual framework for it. To address this gap, 25 experts from 6 continents were brought together to develop guidance. Drawing on multiple peer-reviewed systematic reviews and applying an iterative, anonymous Delphi process, a consensus document was developed and ratified in Melbourne, Australia. The final document contains 58 recommendations - 30 reached unanimous agreement and 28 attained 90-99% agreement. The consensus formally defines fatty pancreas disorder (FPD) as a distinct pathological state, characterized by excessive IPFD that poses a risk to health. Assessment of IPFD is best performed with MRI. Expert-established diagnostic criteria enable identification and classification of FPD. Recognition of type 1 FPD (in individuals without excess body fat mass) and type 2 FPD (in individuals with excess body fat mass) is instrumental in gaining novel insights and tailoring preventive strategies to the individual. The Melbourne consensus is foundational in operationalizing the dissemination of new knowledge in the field, fostering intercontinental collaborations and, ultimately, addressing the global burden of diseases of the pancreas.

INTRODUCTION:The necroptosis regulator PGAM5 drives a pathological cycle of mitochondrial dysfunction and necroptotic signaling, contributing to multi-organ injury and representing a potential therapeutic target. Despite its clinical relevance, few PGAM5-specific small-molecule inhibitors have been developed. OBJECTIVES:We aimed to identify a safe and effective natural small-molecule inhibitor targeting PGAM5 as a novel therapeutic strategy. METHODS:Global PGAM5 knockout mice and pancreas-specific PGAM5 knockdown mice were used to clarify the regulatory role of PGAM5 in pancreatic injury in acute pancreatitis (AP). Subsequently, high-throughput screening of candidate compounds targeting PGAM5 was conducted based on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Combined with molecular docking, in vitro binding experiments, and functional verification experiments, Plantainoside D (PD) was finally identified as a natural small-molecule inhibitor targeting PGAM5. Finally, the protective effect of PD was evaluated using preclinical models of various organ injuries. RESULTS:We identify PGAM5 as a critical mediator of pancreatic acinar cell (PAC) necrosis in AP. Genetic suppression of PGAM5 significantly mitigates PAC necrosis in both in vitro and in vivo AP models. Through high-throughput virtual screening of the TCMSP natural-product database, we identified PD, a phenylethanoid glycoside, as the first reported PGAM5-specific small-molecule inhibitor. By binding PGAM5, PD inhibits its phosphatase activity and prevents oligomerization, thereby restoring mitochondrial homeostasis and blocking necroptosis. Importantly, systemic PD administration demonstrated broad protective efficacy in multiple organ-injury models-including autoimmune hepatitis, acute kidney injury, myocardial ischemia - reperfusion, and lung fibrosis - as well as local efficacy in a pathological high intraocular pressure(ph-IOP) - induced retinal ganglion cell (RGC) injury model. CONCLUSION:These findings establish PGAM5 as a druggable target in organ injury and identify PD as a natural compound with favorable safety and strong translational potential, providing a foundation for necroptosis-targeted therapeutic development.

AIMS:To investigate the associations between intrapancreatic fat deposition (IPFD), quantified by the pancreas-spleen attenuation difference (P-S Difference) on non-enhanced computed tomography (CT), and metabolic biomarkers in Chinese adults, and to distinguish direct and indirect effects of IPFD via body mass index (BMI) and metabolic dysfunction-associated steatotic liver disease (MASLD). MATERIALS AND METHODS:This single-centre, retrospective study analysed 558 Chinese adults (mean age 63.8 ± 13.6 years; 44.4% male). IPFD was quantified as the P-S Difference; lower values indicated greater IPFD. Missing data were handled by multiple imputation. Sequentially adjusted multivariable regression, restricted cubic splines, directed acyclic graph-informed mediation, and stratified analyses were performed. RESULTS:In the fully adjusted model, lower P-S Difference was independently associated with higher fasting plasma glucose (FPG; β = -0.0068, 95% CI -0.0136 to 0.0000; p = 0.049), triglycerides (TG; β = -0.0023, [-0.0043 to -0.0002]; p = 0.028), free fatty acids (FFA; β = -0.0012, [-0.0021 to -0.0003]; p = 0.012), and triglyceride glucose (TyG) index (β = -0.0028, [-0.0046 to -0.0010]; p = 0.002), and with lower high-density lipoprotein cholesterol (HDL-C; β = 0.0013, [0.0002 to 0.0024]; p = 0.025). Associations with clinical diagnoses (hypertension, metabolic syndrome, type 2 diabetes and coronary heart disease) were non-significant after adjustment. BMI mediated ≤ 7.1% of associations, whereas MASLD partially mediated TG (22.5%, p = 0.017) and TyG (15.7%, p = 0.019). CONCLUSIONS:IPFD was associated with an early metabolic signature, notably elevated TG, FFA, and TyG, independent of BMI and MASLD. Prospective validation is required.

Background and Purpose: Health literacy among acute pancreatitis patients is understudied due to the lack of specific assessments. This study aimed to develop and validate the Acute Pancreatitis Health Literacy Scale (APHLS). Methods: A two-phase design was used for APHLS development and initial psychometric validation. Item generation was achieved through cognitive interviews and a Delphi survey, ensuring content relevance and expert consensus. Validity was assessed using content, construct, discriminant, and known-group analyses, while reliability was evaluated through Cronbach's alpha, test-retest reliability, and precision measures. Receiver operating characteristic analysis was conducted to determine the optimal cutoff values for the tool. Results: The final 20-item APHLS showed strong content validity, a three-factor structure confirmed by confirmatory factor analysis, good internal consistency (α = .91), and excellent test-retest reliability (intraclass correlation coefficient = .955). Conclusion: The APHLS is reliable, valid, and practical for assessing health literacy in acute pancreatitis patients and supporting educational interventions.

INTRODUCTION:Pancreatitis and pancreatic cancer lead to excess mortality in the general population. Excessive intrapancreatic fat deposition (IPFD) is a common driver of diseases of the exocrine pancreas according to the PANDORA hypothesis. However, the relationship of IPFD with mortality has never been investigated. We aimed to explore the association of IPFD with mortality. METHODS:Participants from the UK Biobank were divided into 2 cohorts based on the availability of IPFD quantified using MRI. The Kaplan-Meier survival analysis and multivariable Cox-proportional hazard model were used. Genome-wide association study on IPFD and Mendelian randomization analysis were performed. An IPFD-linked polygenic risk score (PRS) was applied in the MRI-naïve cohort. RESULTS:A total of 55,058 participants were analyzed, 695 (1.26%) of whom died during a median follow-up of 4.9 years. Excessive baseline IPFD was significantly associated with an increased risk of all-cause mortality (hazard ratio = 1.081, P < 0.05) and mortality from vascular diseases (hazard ratio = 1.247, P < 0.001). Genome-wide association study identified 38 significant IPFD-associated single nucleotide polymorphisms. The PRS derived from these single nucleotide polymorphism showed significant associations with all-cause mortality and mortality from vascular diseases. In the MRI-naïve cohort of 354,761 participants, consistent results were obtained using the PRS as a genetic proxy for IPFD. DISCUSSION:Excessive IPFD is associated with elevated risk of future mortality especially from vascular diseases in the general population.

Hypertriglyceridemia-associated acute pancreatitis (HTG-AP) is an increasingly recognized cause of acute pancreatitis, particularly in China. This study aims to establish a multi-center prospective cohort to investigate the prevalence, clinical features, recurrence risk, and complications of HTG-AP, and to provide insights into its pathophysiology and management. Chinese Hypertriglyceridemia-associated Pancreatitis Study Group (CHPSG) launched a prospective, multicenter observational study across 12 tertiary hospitals in China. Adult patients with acute pancreatitis and serum triglyceride levels >500 mg/dL are enrolled. Standardized case report forms and biological sample protocols are applied to ensure consistency. Clinical and demographic data and biospecimen are collected at baseline and structured follow-up visits for integrated clinical and translational analyses. The CHPSG consortium enables the enrollment of a geographically diverse patient population and the collection of detailed clinical, genetic, and biomarker data. By utilizing the advantages of multi-center studies, such as external validity and larger sample sizes, CHPSG aims to investigate the prevalence, clinical characteristics, natural history, and risk factors of HTG-AP in China. The consortium will also explore the differences between HTG-AP and other etiologies of pancreatitis, with an emphasis on systemic and local complications, recurrence, and long-term quality of life. Through its phased approach, CHPSG seeks to develop targeted strategies for the prevention and treatment of HTG-AP, ultimately improving patient outcomes. This ongoing prospective study provides a unique platform to bridge clinical observations with mechanistic research. Findings are expected to support precision diagnosis, early identification of complications, and the development of targeted therapeutic interventions for HTG-AP.