To evaluate temporal trends in gender, etiology, severity, outcomes, cost and median length of stay (MLS) in patients with acute pancreatitis (AP) in a third-tier Chinese city.

Patients with AP admitted to a university hospital between January 2013 and December 2021. Relationships between etiology, prevalence of severe acute pancreatitis (SAP) and survey years were investigated by joinpoint regression analysis.

A total of 5459 (male 62.3%) patients with AP were included. Between January 2013 and December 2021, we observed: (a) the prevalence of biliary diseases-related AP was stable, while the prevalence of hypertriglyceridemia (HTG)-associated AP (Ptrend = 0.04) and alcohol-associated AP (Ptrend < 0.0001) both increased; (b) there was an increase in crude prevalence of SAP from 4.97% to 12.2% between 2013 and 2021 (Ptrend < 0.0001); (c) compared to female populations, male gender had a higher prevalence of AP; (d) there was a decrease in MLS from 11 days to 8 days (Ptrend < 0.0001) and in median cost of hospitalization (MCH) for all patients (from 20,166 to 12,845 YUAN) (Ptrend < 0.0001); (e) the overall in-hospital mortality rate was 1.28% (70/5459) for patients with AP. There was no statistically significant in the time trend of mortality during the study period (Ptrend = 0.5873). At multivariate analysis, survey year was associated with prevalence of SAP after adjustment by age and biliary diseases (OR: 1.07; 95% CI: 1.03-1.12). Based on the stratification by severity of disease, the decrease of MLS and MCH was more significant in non-SAP vs. SAP patients.

Over the observational period, the proportion of male patients with AP, prevalence of age-adjusted rate of HTG and alcohol-associated AP and SAP increased, while MLS and MCH for all patients decreased, and the time trend of mortality of AP was stable.

Cytochrome P450 2E1 (CYP2E1) is a key enzyme in the cytochrome P450 family, playing a crucial role in metabolizing a wide range of endogenous and exogenous compounds. It is also pivotal in the onset and progression of inflammation. Despite the demonstrated anti-inflammatory effects of existing CYP2E1 inhibitors in various animal models, their clinical application remains limited due to poor selectivity, high toxicity, degradation susceptibility, and limited in vivo solubility. Through virtual screening, synthesis, and optimization, we identified compound 10 as a favorable selective and potent CYP2E1 inhibitor, with a Kd of 7.02 μM, an IC50 of 1.64 μM, and a Ki of 0.897 μM. Notably, treatment with 10 significantly reduced mortality, inflammation, and oxidative stress in mouse models of severe acute pancreatitis (SAP) induced by Caerulein combined with lipopolysaccharide (LPS) or l-Arginine. 10 significantly promoted the expression of Nrf2 in pancreatic tissues of the two SAP models; in vitro studies revealed that inactivation of Nrf2 signaling and increase of reactive oxygen species (ROS) were reversed by 10 in Caerulein-treated AR42J cells. Overall, our study identified a selective and potent small molecule CYP2E1 inhibitor 10, which may not only serve as a candidate compound for the treatment of SAP but also lay the groundwork for future drug development of anti-inflammatory agents.

Epidemiological evidence suggests that there is a direct relationship between the degree of obesity and acute pancreatitis severity. Intake of different fatty acids leads to different types of hyperlipidemias. Adipose degradation by pancreatic lipase generates different free fatty acids, which can exacerbate pancreatitis. Saturated fatty acids (SFAs) play an inflammatory role in human metabolic syndrome and obesity, whereas unsaturated fatty acids (UFAs) are "good fats" that are thought to enhance overall health status. However, it appears that serum UFAs correlate with severe acute pancreatitis. Additionally, the "obesity paradox" suggests that UFAs potentially minimize direct harm to the organ. This review provides an in-depth overview of the role of SFAs and UFAs in acute pancreatitis of hyperlipidemia and discusses potential prevention targets for severe acute pancreatitis.

Acute pancreatitis (AP) is a common critical disease in clinical practice, characterized by acute onset, rapid progression, aggressive conditions, and high lethality. Pancreatic acinar cell death is a central event in the pathological process of AP and a key factor in determining the extent of local or systemic inflammatory injury and overall prognosis. Programmed cell death (PCD) is a form of active cell death regulated by multiple genes, including apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis. PCD plays a critical role in eliminating unwanted organisms and damaged cells, which is of great significance. Numerous studies have demonstrated a strong association between various forms of PCD and AP, and targeted interventions in PCD signaling pathways and key targets can influence the progression of AP. Furthermore, existing research indicates that natural products sourced from plants, fruits, and vegetables exhibit considerable potential in targeting and regulating PCD for the treatment of AP. Therefore, this paper focuses on summarizing the common types of PCD in AP and discusses the specific signaling pathways and key targets reported in the treatment of AP using natural products. This review aims to provide a reference for natural products in guiding AP treatment and to lay the foundation for developing new drugs to effectively prevent and manage AP.

Severe acute pancreatitis (SAP) is a life-threatening condition characterized by excessive reactive oxygen species (ROS) production and impaired mitochondrial function, resulting from disrupted autophagic flux. Current clinical treatment for SAP fails to address the condition comprehensively, with the treatment targeting only a single pathogenesis. Herein, we report an innovative acid-responsive biomimetic nanozyme. This system features a hollow Prussian blue (PB) core, serving as an ROS scavenger encapsulated within a porous ZIF-8 shell, enabling the efficient delivery of celastrol that activates autophagic flux. Encased in a macrophage membrane, this system selectively targets inflamed pancreatic tissues and is readily internalized by pancreatic acinar cells. This dual-scavenging mechanism effectively attenuates inflammatory cytokine levels and restores mitochondrial homeostasis in three distinct SAP mouse models. Overall, this study presents a promising synergistic strategy for the dual scavenging of damaged mitochondria and ROS, offering a novel therapeutic approach to the treatment of SAP.

Acute pancreatitis (AP) is a common disease in the digestive tract and is characterized by elevated serum pancreatic proteases and abdominal pain. AP, especially severe AP, is still a deadly disease; thus, identifying potential therapies and exploring the underlying mechanism are essential for AP patients. Galangin, a flavonoid extracted from traditional medicinal herbs, shows robust anti-inflammatory and cell protection abilities in various diseases, but its role in AP has not been unveiled. We explored the function and mechanism of galangin in AP using caerulein-induced mouse, isolated acinar cell and bone marrow-derived macrophage models. The pancreas was analyzed using histology and immunofluorescent staining; cytokine levels, the activity of amylase and lipase, and reactive oxygen species (ROS) levels were determined; infiltrating macrophages were analyzed by flow cytometry; certain proteins and RNAs were analyzed; and the safety of galangin was also evaluated. We found that galangin significantly attenuated AP in mice and acinar cells by decreasing ROS and apoptosis via the promotion of Srxn1 expression through an NRF2-dependent pathway. Galangin significantly reduced the number of infiltrating macrophages and inhibited the activation of M1-type macrophages by negatively regulating NF-κB signaling. Compared to the control, no obvious side effects were observed in the galangin-treated group. Thus, our study demonstrated that galangin is a safe and efficient drug to treat AP by preventing injury to acinar cells and inhibiting M1-type macrophages, suggesting a potential therapy for AP in the future.

Acute pancreatitis (AP) is a severe inflammatory condition of the digestive system which, in severe cases, can lead to persistent organ failure (POF). Developing novel therapeutic interventions and diagnostic biomarkers is critical to improve the management and prognosis of this disease. Exosomes, small extracellular vesicles, can reflect the inflammatory state of the pancreas, providing valuable insights into disease progression. Moreover, these vesicles are essential mediators of intercellular communication, modulating inflammatory responses by affecting patterns of cell death and macrophage polarization-key factors in determining AP clinical outcomes. Their stability, bioavailability, and capacity to transport various bioactive molecules render exosomes promising tools for early diagnosis and precision therapy, potentially enhancing patient outcomes. This review highlights the innovative potential of exosomes in transforming the management of AP, providing a foundation for more accurate diagnostics and targeted treatments with clinical applicability.

In acute pancreatitis, interleukin (IL)-22 signaling is increased, whereas overall expression of the cytokine paradoxically drops, suggesting an additional level of control. Here, we investigate the regulation of IL-22 signaling by its soluble neutralizing receptor interleukin-22 binding protein (IL-22BP) in the context of both acute and chronic pancreatitis.

Cerulein was used to induce acute and chronic pancreatitis in both wild-type mice and IL-22BP knockout mice. Histology, multiplex immunofluorescence and flow cytometry were performed to compare differences in tissue injury, recovery, fibrosis, and inflammation at various times of recovery.

Loss of IL-22BP resulted in increased canonical IL-22 signaling and the expression of the anti-autophagy protein Bcl-XL. This was associated with decreased severity of acute pancreatitis, as evidenced by lower serum amylase and tissue injury. In chronic pancreatitis, IL-22BP expression was induced in the inflammatory and recovery phases and genetic deletion resulted in unchecked IL-22 signaling, as demonstrated by persistent p-Stat3 signaling and proliferation of both epithelial cells and fibroblasts. Loss of IL-22BP increased myeloid cell infiltration, which persisted throughout recovery. Mechanistically, IL-22 activity forced persistent acinar to ductal metaplasia and delayed tissue recovery.

IL-22BP plays an important role in modulating IL-22 activity during tissue injury and recovery after pancreatitis. Loss of IL-22BP attenuated acute pancreatitis but promoted chronic fibrosis and inflammation through uncontrolled IL-22 signaling and subsequent deleterious effects on epithelial cells, fibroblasts, and immune infiltration.

This review addresses oxidative stress and redox signaling in the pancreas under healthy physiological conditions as well as in acute pancreatitis, chronic pancreatitis, pancreatic cancer, and diabetes. Physiological redox homeodynamics is maintained mainly by NRF2/KEAP1, NF-κB, protein tyrosine phosphatases, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), and normal autophagy. Depletion of reduced glutathione (GSH) in the pancreas is a hallmark of acute pancreatitis and is initially accompanied by disulfide stress, which is characterized by protein cysteinylation without increased glutathione oxidation. A cross talk between oxidative stress, MAPKs, and NF-κB amplifies the inflammatory cascade, with PP2A and PGC1α as key redox regulatory nodes. In acute pancreatitis, nitration of cystathionine-β synthase causes blockade of the transsulfuration pathway leading to increased homocysteine levels, whereas p53 triggers necroptosis in the pancreas through downregulation of sulfiredoxin, PGC1α, and peroxiredoxin 3. Chronic pancreatitis exhibits oxidative distress mediated by NADPH oxidase 1 and/or CYP2E1, which promotes cell death, fibrosis, and inflammation. Oxidative stress cooperates with mutant KRAS to initiate and promote pancreatic adenocarcinoma. Mutant KRAS increases mitochondrial reactive oxygen species (ROS), which trigger acinar-to-ductal metaplasia and progression to pancreatic intraepithelial neoplasia (PanIN). ROS are maintained at a sufficient level to promote cell proliferation, while avoiding cell death or senescence through formation of NADPH and GSH and activation of NRF2, HIF-1/2α, and CREB. Redox signaling also plays a fundamental role in differentiation, proliferation, and insulin secretion of β-cells. However, ROS overproduction promotes β-cell dysfunction and apoptosis in type 1 and type 2 diabetes.

Acute pancreatitis (AP) ranks among the most frequently encountered gastrointestinal diseases in the emergency department. Recent studies have increasingly emphasized the substantial connection among gut microbiota, inflammatory cytokines, and AP.

A two-sample Mendelian randomization (MR) study was conducted using summary statistics of gut microbiota (GM) from the largest available meta-analysis of genome-wide association studies conducted by the MiBioGen consortium (n=18,340). For cytokines, the data were obtained from a study that investigated genome variant associations with 41 inflammatory cytokines and growth factors (n=8293). The summary statistics of AP were obtained from the FinnGen consortium version R5 data (3022 cases and 195,144 controls). The inverse variance weighted (IVW) method was used as the main analysis, with MR-Egger and weighted median as complementary analytical methods. Sensitivity analyses were performed using Cochran's Q-test, MR-Egger intercept test, leave-one-out analyses, and MR-PRESSO. In addition, we employed the reverse MR analysis and MR Steiger method to estimate the orientations of exposure and outcome.

Among the 211 examined GM taxa, the IVW method revealed that Bacteroidales (odds ratio [OR]=1.412, 95% confidence interval [CI]:1.057 to 1.885, P=0.019), Eubacterium fissicatena group (OR=1.240, 95% CI:1.045 to 1.470, P=0.014), and Coprococcus3 (OR=1.481, 95 % CI:1.049 to 2.090, P=0.026) exhibited a positive association with AP. Conversely, Prevotella9 (OR=0.821, 95% CI:0.680 to 0.990, P=0.038), RuminococcaceaeUCG004 (OR=0.757, 95% CI:0.577 to 0.994, P=0.045), and Ruminiclostridium6 (OR=0.696, 95% CI:0.548 to 0.884, P=0.003) displayed a negative correlation with AP. Among the 41 inflammatory cytokines, only macrophage colony-stimulating factor (M_CSF, OR=0.894, 95% CI:0.847 to 0.943, P=0.037) exhibited a negative association with AP. Sensitivity analyses revealed no evidence of pleiotropy or heterogeneity. Nevertheless, the mediation analysis showed that M_CSF did not act as a mediating factor.

This two-sample MR study revealed causal associations between specific GM and inflammatory cytokines with AP, respectively. However, inflammatory cytokines did not appear to act as mediating factors in the pathway from GM to AP.

Acute organ injuries represent a major public health concern, driven by inflammation and mitochondrial dysfunction, leading to cell damage and organ failure. In this study, we engineered neutrophil membrane-fused mitochondria (nMITO), which combine the injury-targeting and anti-inflammatory properties of neutrophil membrane proteins with the cell repairing function of mitochondria. nMITO effectively blocked inflammatory cascades and restored mitochondrial function, targeting both key mechanisms in acute organ injuries. In addition, nMITO selectively targeted damaged endothelial cells via β-integrins and were delivered to injured tissues through tunneling nanotubes, enhancing their regulatory effects on inflammation and cell damage. In mouse models of acute myocardial injury, liver injury, and pancreatitis, nMITO notably reduced inflammatory responses and repaired tissue damage. These findings suggest that nMITO is a promising therapeutic strategy for managing acute organ injuries.

Pancreatitis, as a common exocrine pancreatic disease, poses a daunting challenge to patients' health and the medical system. Endoplasmic reticulum stress (ERS) plays an essential role in the pathologic process of pancreatitis. However, its mechanism is not fully understood. Therefore, this study was designed to deepen the understanding of the pathogenic mechanism of the disease by screening key ERS-related genes (ERSRGs) associated with pancreatitis. Pancreatitis mRNA data for GSE194331 (Normal: 32, Pancreatitis: 87) and pancreatitis GSE143754 (Normal: 9, Pancreatitis: 6) were downloaded from the GEO database and were used as a training and validation set, respectively. First, the training set GSE194331 was differentially expressed and intersected with the ERSRGs (n = 265) obtained from the MSigDB database to result in 42 differentially expressed ERSRGs (DE-ERSRGs). Subsequently, five candidate genes were further screened by PPI network and MCC and MCODE algorithms. However, according to the ROC curve results, AUC values of CCND1, BCL2, PIK3R1, and BCL2L1 were all greater than 0.6, indicating that they had good diagnostic performance, which was verified by the GSE143754 data set. Based on the GeneMANIA network, it was found that hub genes BCL2 and BCL2L1 may be the key factors in the regulation of mitochondrial metabolism. 24 differentially expressed pancreatitis-related genes (DE-PRGs) were found by difference analysis and Venn analysis. Hub genes BCL2 and PIK3R1 that were significantly correlated with 24 DE-PRGs were determined by Spearman analysis. ssGSEA algorithm was further used to reveal the significant correlation between these hub genes and the immune microenvironment of pancreatitis. The miRNA and lncRNA targeting hub genes were predicted using miRWalk, TargetScan, miRDB, and ENCORI databases, providing research directions for the mechanism of pancreatitis. Finally, the Network Analyst website was used to predict potential compounds associated with the hub gene. In conclusion, this study not only further supports the role of ERS in the development of pancreatitis but also provides a new perspective and direction for the development of biomarkers and mechanism of pancreatitis. At the same time, the results of this study provide a reliable research direction for the targeted treatment of pancreatitis.

Acute pancreatitis (AP) initiates as primarily sterile local inflammation that triggers pro-inflammatory response, which is subsequently counterbalanced by an anti-inflammatory response. Immune checkpoints, such as PD-1/PD-L1, play a pivotal role in modulating these responses to prevent excessive immune activation and associated inflammatory damage. This study aimed to investigate the underlying mechanisms of these processes in both murine and human AP.

We conducted a comprehensive integration of data from cerulein-induced AP mouse models (CER-AP), utilizing single-cell RNA sequencing and digital spatial profiling for pancreatic samples, as well as single-cell Cytometry by Time Of Flight (CyTOF) for blood samples. Additionally, bulk-RNA sequencing performed on blood samples from AP patients was employed to investigate innate and adaptive immune changes at early stage of the disease.

Across the four analytical approaches, we observed consistent immune cell type distributions. Our integrative analysis revealed a significant imbalance between increased innate immune cells, including neutrophils, macrophages, and monocytes, and decreased adaptive immune cells, including CD4+ and CD8+ T cells, in early-stage AP. Notably, the PD-1/PD-L1 related pathway exhibited substantial alterations, especially in the acinar cells, T cells, B cells, macrophages, and neutrophils at the early stage of disease. Moreover, we observed a significant reduction in PD-L1 expression in the blood and regulatory T cells of CyTOF mice at the CyTOF level.

This multi-omics analysis deciphers a distinct imbalance between increased innate immunity and decreased adaptive immunity during the early phase of AP. The PD-L1 checkpoint emerges as a key regulator of immune homeostasis and a critical factor in the pathogenesis of AP.

Acute pancreatitis (AP) is a serious inflammatory disease with high incidence rate and mortality. It was confirmed that overactivation of autophagy in acinar cells can increase the risk of AP. Nevertheless, the regulatory mechanism of autophagy in AP is unclear. The role of ubiquitin-specific peptidase 7 (USP7) in controlling autophagy during AP development was examined in this study. AR42J cells were subjected to caerulein to establish a cell model of AP. ELISA utilized to assess IL-6, IL-1β, and TNF-α secretion levels. Cell viability and death were detected using CCK8 assay and flow cytometry, respectively. The interaction between USP7 and ATF4 was analyzed by Co-IP assay. USP7 and ATF4 were abnormally overexpressed in AP patients and cellular models. Loss of function of USP7 increased cell viability, but alleviated cell death and secretions of inflammatory cytokines including IL-6, IL-1β, and TNF-α in AP cellular models. Importantly, autophagy level was activated in AP cells, and could be repressed after USP7 knockdown, and rapamycin treatment greatly diminished the beneficial functions mediated by USP7 downregulation in AP cells. Mechanically, ATF4, an activator of stress autophagy in AP, was proved to be a deubiquitination modification target downstream of USP7, and its protein stability was weakened after USP7 reduction. ATF4 upregulation abolished the protective effect of USP7 silencing on caerulein-induced autophagy, inflammation, and cell injury in AR42J cells. USP7 knockdown reduced inflammation and cell injury during AP progression by inhibiting ATF4-mediated autophagy activation.

To investigate the role of quercetin-added pancreatic prescription food in regulating metabolic homeostasis in dogs.

The experimental dogs were divided into a control diet group and a prescription diet group. The control group was fed regular food, while the prescription group was fed pancreatic prescription food (3.9 g of quercetin was added in per 1 kg of food) for 8 weeks. Canine physical examination, complete blood count, and serum biochemical tests were conducted at 0 w, 4 w, and 8 w. Non-targeted metabolomics tests were performed using plasma samples at 0 w and 8 w.

Dogs that received a quercetin-added pancreatic diet supplemented with quercetin showed no changes in the body weight, fasting blood glucose, body condition score, the indexes of whole blood program of red blood cells, white blood cells and platelets, and most blood biochemical indexes, but increased lipase levels in plasma at 8 w. Quercetin significant improved in metabolic homeostasis, especially in fatty acid, amino acid, and bile acid metabolism. Untargeted metabolomics analysis revealed that quercetin activates ABC transport and arginine/proline pathways, suggesting potential benefits for pancreatitis in large animals, while maintaining comparable safety parameters.

Quercetin-added prescription food enhances fatty acid and amino acid metabolism, demonstrating its potential to promote pancreatic function and sustain metabolic homeostasis.

Current point-of-care testing for canine-specific pancreatic lipase (CPL) provides semi-quantitative measurements with binary results. Recently, a commercial point-of-care testing method (Vcheck CPL) that offers quantitative measurement of CPL has emerged. However, clinical studies on its value (or utility) are limited. Therefore, this study aimed to evaluate the clinical utility of this commercial point-of-care CPL in diagnosing dogs with suspected acute pancreatitis and to assess its correlation with a commercial semi-quantitative test and other clinicopathological variables.

A prospective observational study included 33 dogs with suspected acute pancreatitis and 20 clinically healthy dogs. Serum Vcheck CPL and SNAP ® cPL were tested, and clinical consensus scores were determined by 5 internists. Eleven dogs with suspected acute pancreatitis underwent follow-up testing during hospitalization. The intra-class correlation coefficient (ICC) was used for statistical analysis to assess the agreement between assays and the internists' consensus score.

Dogs with suspected acute pancreatitis had significantly higher serum Vcheck CPL (median: 843 μg/L, range: 77-2001, p < 0.0001) than healthy control dogs (median: 94 μg/L, range: 49-294). By day 3 of hospitalization, serum Vcheck CPL had significantly decreased in dogs with suspected acute pancreatitis compared to day 1. The ICC score between the clinical consensus score, Vcheck CPL, and SNAP ® cPL was 0.75, indicating good agreement. Serum Vcheck CPL concentration was significantly correlated with serum concentrations of amylase, lipase, creatinine, ALP, and CRP.

This study found good agreement between Vcheck CPL and SNAP ® cPL. This quantitative Vcheck CPL testing could serve as an adjunctive tool in diagnosing dogs with acute pancreatitis.

Microglia activation and autophagy changes are associated with the regulation of pain, but no study to date has been designed to address whether these features apply to trigeminal neuropathic pain. This study aimed to investigate how alterations in autophagy affect nociceptive behaviors may be associated with microglia activation in the caudal part of the spinal trigeminal nucleus (SpVC) in a rat model of trigeminal neuropathic pain. This model was established by chronic constriction injury of the infraorbital nerve. Autophagy inhibitors and agonists were injected into the lateral ventricle to regulate autophagy. The autophagy markers microtubule-associated protein light chain 3 I (LC3-I), LC3-II, sequestosome1 (p62), and LC-3 were examined by western blotting and/or immunofluorescence. The microglia marker ionized calcium binding adapter molecule 1 (Iba-1) was examined by immunohistochemistry. Nociceptive behavior changes were detected by measuring the mechanical thresholds and face-grooming duration. The results showed that microglia in SpVC were activated, and autophagy flux was blocked in the trigeminal neuropathic pain model. Autophagy agonists inhibited microglia activation and alleviated nociceptive behaviors. In contrast, autophagy inhibitors further activated microglia and exacerbated nociceptive behaviors. In a rat model of trigeminal neuropathic pain, autophagy blockage leads to microglia activation, which significantly influences nociceptive processes.

The IL-2 family, consisting of IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, is a key regulator of the immune response. As an important endocrine and digestive organ, the function of the pancreas is regulated by the immune system. Studies have shown that each cytokine of the IL-2 family influences the occurrence and development of pancreatic diseases by participating in the regulation of the immune system. In this paper, we review the structural and functional characteristics of IL-2 family members, focus on their molecular mechanisms in pancreatic diseases including acute pancreatitis, chronic pancreatitis and pancreatic cancer, and highlight the importance of the related proteins in the regulation of immune response and disease progression, which will provide valuable insights for new biomarkers in pancreatic diseases, early diagnosis of the diseases, assessment of the disease severity, and development of new therapeutic regimens. The insights of the study are summarized in the following sections.

Obesity is a significant risk factor for severe acute pancreatitis (SAP) and is typically associated with increased intestinal permeability. Understanding the role of specific molecules can help reduce the risk of developing SAP. Claudin 11 (CLDN11), a member of the Claudin family, regulates the permeability of various internal barriers. However, the role and mechanism of CLDN11 in the intestinal permeability of obesity-related SAP remain unclear.

We evaluated intestinal permeability and the expression of CLDN11 in experimental obesity-related SAP. A recombinant adeno-associated virus carrying CLDN11 was used to treat experimental obesity-related SAP. The interaction between CLDN11 mRNA and insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) protein was predicted through bioinformatics analysis and validated by RNA immunoprecipitation and RNA pull-down assay. Additionally, tumor necrosis factor-α (TNF-α) treatment in Caco-2 cells was conducted, and the IGF2BP3/CLDN11 axis was detected. Moreover, we conducted anti-TNFα therapy and evaluated intestinal permeability and pancreatic inflammation in experimental obesity-related SAP.

Downregulation of CLDN11 was observed in the intestinal epithelial cells of experimental obesity-related SAP. When the expression of CLDN11 in intestinal epithelial cells of experimental obesity-related SAP was increased exogenously, intestinal epithelial permeability and pancreatic inflammation were relieved. Overexpression of CLDN11 reduced the paracellular permeability of Caco-2 monolayer cells, while knockdown of CLDN11 increased it. IGF2BP3 bound to and regulated the stability of CLDN11 mRNA. TNF-α treatment downregulated IGF2BP3 and CLDN11 in vitro. Anti-TNFα therapy reduced intestinal permeability, alleviated pancreatitis, and improved the expression of IGF2BP3 and CLDN11 in intestinal epithelial cells in experimental obesity-related SAP.

CLDN11 regulates intestinal permeability in obesity-related SAP. Mechanistically, an increase in TNF-α impaired the stability of IGF2BP3-dependent CLDN11 mRNA in obesity-related SAP.

Acute pancreatitis is an inflammatory condition of the exocrine pancreas that is a common indication for hospital admission and has had an increasing incidence in the last few decades. The diagnosis of acute pancreatitis requires the satisfaction of two out of three criteria: (1) abdominal pain radiating to the back, (2) serum lipase or amylase levels three or more times the upper limit of the normal level, and (3) findings indicating pancreatitis obtained via a computed tomography (CT) scan or magnetic resonance imaging (MRI). The different etiologies include gallstones, autoimmune disorders, alcohol abuse, smoking, hypertriglyceridemia, obesity, drugs, and post-endoscope retrograde cholangiopancreatography (ERCP). The initial investigation includes serum amylase and lipase analysis, a lipid panel including triglycerides, analysis of immunoglobulins, a full blood count, electrolyte analysis, a hemoglobin A1c test, a complete metabolic panel, and transabdominal ultrasound. The initial therapy includes oxygen supplementation, the provision of intravenous fluids, pain control, and a nutrition regime. Early oral feeding is encouraged if tolerated; if not, liquid supplement provision or enteral tube feeding within 48 h of admission has shown better outcomes. Some complications of acute pancreatitis are necrosis, infection, insulin resistance leading to diabetes mellitus, and pancreatic exocrine insufficiency requiring enzyme supplementation. Patients need to attend regular follow-ups and abstain from alcohol and smoking (if warranted) to prevent the recurrence of acute pancreatitis. The mortality rate of acute pancreatitis has decreased in the past few decades because of better management skills, but the recent rise in acute pancreatitis episodes is concerning. Sustained endeavors through clinical trials are required to establish a broad variety of drugs that can be used for acute pancreatitis episodes.

To investigate the early dynamic changes of biomarkers associated with capillary leak syndrome (CLS) in patients with severe acute pancreatitis (SAP) and their correlation with multiple organ failure (MOF).

A total of 171 SAP patients admitted to the West China Centre of Excellence for Pancreatitis, West China Hospital, Sichuan University between September 1, 2019 and December 31, 2020 were enrolled for this study. The patients were divided into MOF and non-MOF groups based on the occurrence of MOF in the first 5 days of hospitalization, and were further divided into subgroups based on the presence of moderate-to-severe intra-abdominal hypertension (IAH). We performed dynamic monitoring of the blood biomarkers (hematocrit [HCT], blood urea nitrogen [BUN], and creatinine [Cr]), plasma proteins (albumin [Alb], total protein [TP], and non-albumin plasma proteins [NAPP]), and intra-abdominal pressure. Trends in these indicators across groups were analyzed comprehensively.

No significant differences in baseline data between the two groups were observed. The baseline data of the 2 groups were comparable. The MOF group had significantly higher rates of persistent systemic inflammatory response syndrome (SIRS) lasting 48 hours (91.3% vs. 71.8%), ICU admission (70.4% vs. 17.6%), and length-of-stay ([32 ± 17.7] days vs. [19.0 ± 12.2] days) compared to those of the non-MOF group (P < 0.05). The incidences of respiratory, circulatory, and renal failures were higher in the MOF group than those in the non-MOF group, showing significant differences in circulatory failure (69% vs. 3.5%) and renal failure (65.5% vs. 3.5%) (P < 0.05). In the first 5 days of hospitalization, the MOF group showed significantly elevated BUN and Cr levels, while Alb and TP levels dropped rapidly upon admission and then gradually recovered. The NAPP level of the MOF group continued to decrease after admission, and on the third day after admission, the NAPP level was lower than that of the Non-MOF group, showing statistically significant difference (P < 0.001). The Alb/NAPP ratio of the MOF group decreased significantly on day 1 and then rapidly increased, showing significant differences between the groups on days 3 and 4 (P = 0.001). Subgroup analysis of MOF patients with moderate-to-severe IAH revealed similar trends in the dynamic changes and the overall changes in the indicators, and the difference was even more pronounced. The mixed linear model showed that the average levels of HCT, BUN, Alb/NAPP, and Alb/TP were higher and increased over time in the MOF combined with IAP subgroup (P < 0.001).

The CLS model of SAP patients is validated, confirming that CLS is a key factor in the progression from SIRS to MOF. The loss of NAPP is an early and important indicator of CLS persistence and progression to MOF. Additionally, moderate-to-severe IAH accelerates the deterioration of MOF. These findings provide valuable insights into the potential mechanisms of MOF and warrant further validation through large-scale prospective studies.

Acute pancreatitis (AP) represents a severe inflammatory condition of the exocrine pancreas, precipitating systemic organ dysfunction and potential failure. The global prevalence of acute pancreatitis is on an ascending trajectory. The condition carries a significant mortality rate during acute episodes. This underscores the imperative to elucidate the etiopathogenic pathways of acute pancreatitis, enhance comprehension of the disease's intricacies, and identify precise molecular targets coupled with efficacious therapeutic interventions. The pathobiology of acute pancreatitis encompasses not only the ectopic activation of trypsinogen but also extends to disturbances in calcium homeostasis, mitochondrial impairment, autophagic disruption, and endoplasmic reticulum stress responses. Notably, the realm of epigenetic regulation has garnered extensive attention and rigorous investigation in acute pancreatitis research over recent years. One of these modifications, lysine acetylation, is a reversible post-translational modification of proteins that affects enzyme activity, DNA binding, and protein stability by changing the charge on lysine residues and altering protein structure. Numerous studies have revealed the importance of acetylation modification in acute pancreatitis, and that it is a favorable target for the design of new drugs for this disease. This review centers on lysine acetylation, examining the strides made in acute pancreatitis research with a focus on the contributory role of acetylomic alterations in the pathophysiological landscape of acute pancreatitis, thereby aiming to delineate novel therapeutic targets and advance the development of more efficacious treatment modalities.

Acute pancreatitis (AP) is a prevalent and serious condition within the digestive system, with approximately 20 % to 30 % of cases advancing to severe acute pancreatitis (SAP). During the initial phases of SAP, macrophages are activated in response to the substantial amounts of acinar cell contents and damage-associated molecular patterns (DAMPs) resulting from acinar cell destruction. Subsequently, activated macrophages release a significant array of pro-inflammatory factors that exacerbate the progression of SAP. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncogenic protein that is intimately linked to immune regulation. While the role of CIP2A in T-cell-mediated specific immune responses has been reported, its function and mechanism in macrophages, a component of non-specific immunity, have not been widely studied. This research fills this knowledge gap by elucidating the critical role of CIP2A in regulating macrophage autophagy and inflammation. This finding not only expands our understanding of CIP2A in immune modulation but also provides a new scientific basis and potential application prospects for targeting CIP2A in the treatment of AP.

We established AP using a combination of palmitoleic acid with anhydrous ethanol or using caerulein alone. The effects of TD52 and Ethoxysanguinarine (Etho) on SAP were evaluated through serological, histopathological, and tissue inflammation observations. The effect of TD52 on macrophage activation in vitro was examined using primary macrophages (PMs) and RAW264.7 cells.

We found that TD52 and Etho inhibit CIP2A expression while reducing the levels of serum amylase, lipase, and inflammatory cytokines, thereby alleviating the pathological symptoms of SAP. Additionally, TD52 could reduce the infiltration of macrophages into pancreatic tissue. Therefore, we established a model of macrophage inflammatory response mimicking the pathophysiological process of AP and detected changes in inflammation, apoptosis, and autophagy through pre-treatment of macrophages with TD52. The results show that inhibiting CIP2A expression decreases the release of inflammatory cytokines and reduces apoptosis in macrophages. Further exploration revealed that TD52 promoted macrophage autophagy regulation and inhibited the AKT-mTOR pathway to modulate macrophage activation.

In summary, our findings indicate that TD52 and Etho can alleviate the severity of SAP. TD52 can block the AKT-mTOR pathway to promote macrophage autophagy, thereby improving SAP. Thus, CIP2A may serve as one of the molecular targets in SAP, highlighting its potential as a therapeutic option.

Co-crystallization of a therapeutic ingredient with an appropriate co-former is a powerful technique to augment the physicochemical and pharmacokinetic properties and the effectiveness of Active Pharmaceutical Ingredients (APIs). Biochanin A (BCA), a flavonoid with medicinal potential, is limited by poor solubility and low oral bioavailability. This study aimed to design and develop a novel BCA-nicotinamide cocrystal as BCC to enhance BCA's oral bioavailability and explore its therapeutic potential for ameliorating cerulein-induced acute pancreatitis (CIAP) by elucidating the target identification utilizing tissue/serum metabolite profiles. The cocrystal was designed by the supramolecular synthon approach and characterized by single-crystal X-ray diffraction that confirms a robust three-dimensional hydrogen-bonded network of BCA and Nicotinamide (NCT) in the crystal. FT-IR and DSC were used to analyze the cocrystal's intermolecular interactions and thermal behavior. BCC exhibited enhanced solubility and drug release compared to BCA alone, resulting in enhanced oral bioavailability and pancreatic tissue concentration. Comparing BCC to BCA in the CIAP model, BCC therapy remarkably reduced cerulein-induced pancreatitis, evidenced by significant reductions in inflammation, acinar cell atrophy, and amylase levels in pancreatic tissues. Further, the cocrystal formulation also down-regulated the oxidative stress markers, inflammatory cytokines and macrophage-related proteins. The study has identified distinct metabolomic signatures linked with AP with the help of Orbitrap Exploris mass spectrometry, which could pave the way for creating focused diagnostic tools for a better prognosis. In conclusion, these results offer new insights into exploring mechanistic pathways associated with specific biomarkers and underscore BCC cocrystal as a promising approach to enhance BCA's therapeutic potential.

Severe acute pancreatitis (SAP) is an acute inflammatory injury disease with significant mortality rate and currently without effective strategy being available. Inflammation and oxidative stress play central roles in the etiology of SAP. Micheliolide (MCL), an active monomeric component isolated from Michelia champaca, has been proved its multiple therapeutic properties including anti-inflammatory, antioxidant and anti-cancer. Nevertheless, the therapeutic effect and underlying mechanism of MCL in SAP still remain unclear. Here, we found that caerulein with lipopolysaccharide (LPS)-induced SAP murine models exhibited severe pancreatic injury, including necrosis, edema, and vacuolation of acinar cells in the pancreas, elevated serum levels of amylase and lipase, and reduced number of the exocrine cells. As expected, MCL treatment alleviated these side effects. Mechanistically, MCL triggered nuclear factor erythroid 2-related factor 2 (Nrf2) activation, thereby activating Nrf2-regulated antioxidative pathways and inhibiting nuclear factor kappa B p65 (NF-κB p65)-mediated inflammatory response, resulting in protection against pancreatic injury in SAP mice. In addition, Nrf2 gene deficiency abolished the beneficial effects of MCL on SAP-induced pancreatic inflammation and oxidative stress and blocked the ability of MCL to alleviate the pancreatic injury in SAP mice. Collectively, these findings indicated that the suppression of SAP-induced pancreatic injury by MCL was at least in part due to Nrf2-mediated anti-oxidation effect and inhibition of inflammation.

Acute pancreatitis (AP) is an inflammatory disease of the pancreas and a complex process involving multiple factors, with mitochondrial damage playing a crucial role. Mitochondrial dysfunction is now considered a key driver in the development of AP. This dysfunction often presents as increased oxidative stress, altered membrane potential and permeability, and mitochondrial DNA damage and mutations. Under stress conditions, mitochondrial dynamics and mitochondrial ROS production increase, leading to decreased mitochondrial membrane potential, imbalanced calcium homeostasis, and activation of the mitochondrial permeability transition pore. The release of mitochondrial DNA (mtDNA), recognized as damage-associated molecular patterns, can activate the cGAS-STING1 and NF-κB pathway and induce pro-inflammatory factor expression. Additionally, mtDNA can activate inflammasomes, leading to interleukin release and subsequent tissue damage and inflammation. This review summarizes the relationship between mitochondria and AP and explores mitochondrial protective strategies in the diagnosis and treatment of this disease. Future research on the treatment of acute pancreatitis can benefit from exploring promising avenues such as antioxidants, mitochondrial inhibitors, and new therapies that target mitochondrial dysfunction.

Serum amylase (AMY) levels measured 2-6 h after ERCP are a predictor of post-ERCP pancreatitis (PEP). Trypsin is one of the pancreatic enzymes elevated in the development of PEP. The study assessed whether serum trypsin (TRY) can predict early-stage PEP.

This prospective study included patients who underwent ERCP from June 2022 to May 2023. TRY, AMY, serum pancreatic AMY (P-AMY), and serum lipase (LIP) levels were measured immediately after ERCP and 2 h later. The primary outcome was the diagnostic abilities of TRY levels measured immediately (0 h-TRY) and 2 h after (2 h-TRY) ERCP to predict PEP (compared with the other serum pancreatic enzymes).

Of 130 patients analyzed, 18 developed PEP. The sensitivity and specificity of 0 h-TRY were 83.3% and 69.6%, respectively, and those of 2 h-TRY were 88.9% and 72.3%, respectively. The area under the curve (AUC) for 0 h-TRY was significantly higher than that for 0 h-AMY (p = .006) and 0 h-P-AMY (p = .012), whereas the AUCs for 0 h-TRY and 0 h-LIP did not differ significantly (p = .563). The AUC for 2 h-TRY for predicting PEP was significantly higher than that for 2 h-AMY (p = .025), whereas there was no significant differences between the AUCs for 2 h-TRY and 2 h-P-AMY(p = .146), or between those for 2 h-TRY and 2 h-LIP (p = .792). The median increase ratio (expressed as a ratio relative to baseline) in TRY was highest among all of serum pancreatic enzymes tested immediately after ERCP (5.35, 1.72, 1.94, and 4.44 for TRY, AMY, P-AMY, and LIP, respectively).

Measuring TRY immediately after ERCP is useful for the early prediction of PEP.

Exogenous inhibition of neutrophil extracellular traps (NETs) was believed to alleviate acute pancreatitis (AP). This study aimed to comprehensively explore the key biological behavior of NETs including timing and pathogenesis in AP by integrating of single cell RNA sequencing(scRNA-seq) and bulk RNA-seq.

Differentially expressed NETs-related genes and the hub genes of NETs were screened by bulk RNA-seq. ScRNA-seq was used to identify the cell types in pancreas of AP mice and to depict the transcriptomic maps in neutrophils. The mouse AP models were build to verify the timing of initiation of NETs and underlying pathogenesis of damage on pancreas acinar cells.

Tlr4 and Ccl3 were screened for hub genes by bulk RNA-seq. The trajectory analysis of neutrophils showed that high expression of Ccl3, Cybb and Padi4 can be observed in the middle stage during AP. Macrophages might be essential in the biological behavior of neutrophils and NETs. Through animal models, we presented that extensive NETs structures were formed at mid-stage of inflammation, accompanied by more serious pancreas and lung damage. NETs might promote necroptosis and macrophage infiltration in AP, and the damage on pancreatic injury could be regulated by Tlr4 pathway. Ccl3 was considered to recruit neutrophils and promote NETs formation.

The findings explored the underlying timing and pathogenesis of NETs in AP for the first time, which provided gene targets for further studies.

Pancreatitis is a common, life-threatening inflammatory disease of the exocrine pancreas. Its pathogenesis remains obscure, and no specific or effective treatment is available. Gallstones and alcohol excess are major etiologies of pancreatitis; in a small portion of patients the disease is hereditary. Pancreatitis is believed to be initiated by injured acinar cells (the main exocrine pancreas cell type), leading to parenchymal necrosis and local and systemic inflammation. The primary function of these cells is to produce, store, and secrete a variety of enzymes that break down all categories of nutrients. Most digestive enzymes, including all proteases, are secreted by acinar cells as inactive proforms (zymogens) and in physiological conditions are only activated when reaching the intestine. The generation of trypsin from inactive trypsinogen in the intestine plays a critical role in physiological activation of other zymogens. It was proposed that pancreatitis results from proteolytic autodigestion of the gland, mediated by premature/inappropriate trypsinogen activation within acinar cells. The intra-acinar trypsinogen activation is observed in experimental models of acute and chronic pancreatitis, and in human disease. On the basis of these observations, it has been considered the central pathogenic mechanism of pancreatitis - a concept with a century-old history. This review summarizes the data on trypsinogen activation in experimental and genetic rodent models of pancreatitis, particularly the more recent genetically engineered mouse models that mimic mutations associated with hereditary pancreatitis; analyzes the mechanisms mediating trypsinogen activation and protecting the pancreas against its' damaging effects; discusses the gaps in our knowledge, potential therapeutic approaches, and directions for future research. We conclude that trypsin is not the culprit in the disease pathogenesis but, at most, a mediator of some pancreatitis responses. Therefore, the search for effective therapies should focus on approaches to prevent or normalize other intra-acinar pathologic processes, such as defective autophagy leading to parenchymal cell death and unrelenting inflammation.

Damage to pancreatic acinar cells (PAC) and intracellular metabolic disturbances play crucial roles in pancreatic necrosis during acute pancreatitis (AP). Phosphoglycerate kinase 1 (PGK1) is a crucial catalytic enzyme in glycolysis. However, the impact of PGK1-involving glycolysis in regulating metabolic necrosis in AP is unclear. Transcriptome analysis of pancreatic tissues revealed significant changes in the glycolysis pathway and PGK1 which positively correlated with the inflammatory response and oxidative stress injury in AP mice. Furthermore, we observed a substantial increase in PGK1 expression in damaged PAC, positively correlating with PAC necrosis. Treatment with NG52, a specific PGK1 inhibitor, ameliorated pancreatic necrosis, inflammatory damage, and oxidative stress. Transcriptomic data before and after NG52 treatment along with the Programmed Cell Death database confirmed that NG52 protected against PAC damage by rescuing impaired autophagy in AP. Additionally, the protective effect of NG52 was validated following pancreatic duct ligation. These findings underscore the involvement of PGK1 in AP pathogenesis, highlighting that PGK1 inhibition can mitigate AP-induced pancreatic necrosis, attenuate inflammatory and oxidative stress injury, and rescue impaired autophagy. Thus, the study findings suggest a promising interventional target for pancreatic necrosis, offering novel strategies for therapeutic approaches to clinical AP.

Gastrointestinal disorders encompass a spectrum of conditions affecting various organs within the digestive system, such as the esophagus, stomach, colon, rectum, pancreas, liver, small intestine, and bile ducts. The role of autophagy in the etiology and progression of gastrointestinal diseases has garnered significant attention. This paper seeks to evaluate the impact and mechanisms of autophagy in gastrointestinal disorders by synthesizing recent research findings. Specifically, we delve into inflammation-related gastrointestinal conditions, including ul-cerative colitis, Crohn's disease, and pancreatitis, as well as gastrointestinal cancers such as esophageal, gastric, and colorectal cancers. Additionally, we provide commentary on a recent publication by Chang et al in the World Journal of Gastroenterology. Our objective is to offer fresh perspectives on the mechanisms and therapeutic approaches for these gastrointestinal ailments. This review aims to offer new perspectives on the mechanisms and therapeutic strategies for gastrointestinal disorders by critically analyzing relevant publications. As discussed, the role of autophagy in gastrointestinal diseases is complex and, at times, contentious. To harness the full therapeutic potential of autophagy in treating these conditions, more in-depth research is imperative.

Introduction: Acute necrotizing pancreatitis (ANP) is the acute inflammation of pancreatic parenchyma, most commonly due to alcohol abuse or cholelithiasis. The treatment can be either conservative or invasive, including a variety of techniques; however, it has not yet been established if the intervention should be early or if it should be delayed. The aim of this review is to investigate the optimal time for intervention in ANP. Methods: A literature search was conducted in PubMed and Scopus from inception until September 2024 for studies reporting the comparison between early and late intervention. Results: Early intervention, within 4 weeks of symptom onset, often involves drainage via percutaneous, endoscopic, or combined methods. Delayed intervention occurs after 4 weeks of symptom onset. This can be conducted either surgically or via minimally invasive means. The results of this review reveal that the time of intervention for ANP plays an important role in the prognosis and the course of the disease. In particular, early intervention is associated with higher mortality, which is also the primary clinical outcome. Delayed intervention is also superior regarding secondary clinical outcomes, specifically the complications associated with the intervention. Thus, it is accompanied by fewer episodes of new-onset organ failure, bleeding, gastrointestinal fistula, pancreatic fistula, wound infection, endocrine pancreatic insufficiency, and other complications. Finally, delayed intervention results in shorter stays, both in hospitals and the ICU. Conclusions: Delayed intervention is clearly more effective than early intervention and should be preferred. However, early intervention appears to be both safe and effective, and it is feasible.

Previous research has shown that the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in macrophages can promote severe acute pancreatitis through the release of inflammatory factors. The role of this pathway in pancreatic acinar cells, however, has not been studied, and understanding its mechanism could be crucial. We analysed plasma from 50 acute pancreatitis (AP) patients and 10 healthy donors using digital PCR, which links mitochondrial DNA (mtDNA) levels to the severity of AP. Single-cell sequencing of the pancreas during AP revealed differentially expressed genes and pathways in acinar cells. Experimental studies using mouse and cell models, which included mtDNA staining and quantitative PCR, revealed mtDNA leakage and the activation of STING-related pathways, indicating potential inflammatory mechanisms in AP. In conclusion, our study revealed that the mtDNA-STING-nuclear factor κB(NF-κB) pathway in pancreatic acinar cells could be a novel pathogenic factor in AP.

Mitochondria play a crucial role in maintaining the normal physiological state of cells. Hence, ensuring mitochondrial quality control is imperative for the prevention and treatment of numerous diseases. Previous reviews on this topic have however been inconsistencies and lack of systematic organization. Therefore, this review aims to provide a comprehensive and systematic overview of mitochondrial quality control and explore the possibility of targeting the same for the treatment of major diseases. This review systematically summarizes three fundamental characteristics of mitochondrial quality control, including mitochondrial morphology and dynamics, function and metabolism, and protein expression and regulation. It also extensively examines how imbalances in mitochondrial quality are linked to major diseases, such as ischemia-hypoxia, inflammatory disorders, viral infections, metabolic dysregulations, degenerative conditions, and tumors. Additionally, the review explores innovative approaches to target mitochondrial quality control, including using small molecule drugs that regulate critical steps in maintaining mitochondrial quality, nanomolecular materials designed for precise targeting of mitochondria, and novel cellular therapies, such as vesicle therapy and mitochondrial transplantation. This review offers a novel perspective on comprehending the shared mechanisms underlying the occurrence and progression of major diseases and provides theoretical support and practical guidance for the clinical implementation of innovative therapeutic strategies that target mitochondrial quality control for treating major diseases.

Pancreatic adenocarcinoma is one of the most lethal types of gastrointestinal cancer despite the latest medical advances. Its incidence has continuously increased in recent years in developed countries. The location of the pancreas can result in the initial symptoms of neoplasia being overlooked, which can lead to a delayed diagnosis and a subsequent reduction in the spectrum of available therapeutic options. The role of modifiable risk factors in pancreatic cancer has been extensively studied in recent years, with smoking and alcohol consumption identified as key contributors. However, the few screening programs that have been developed focus exclusively on genetic factors, without considering the potential impact of modifiable factors on disease occurrence. Thus, fully understanding and detecting the risk factors for pancreatic cancer represents an important step in the prevention and early diagnosis of this type of neoplasia. This review reports the available evidence on different risk factors and identifies the areas that could benefit the most from additional studies.

The rapidly aging population is consuming more alcohol, leading to increased alcohol-associated acute pancreatitis (AAP) with high mortality. However, the mechanisms remain undefined, and currently there are no effective therapies available. This study aims to elucidate aging- and alcohol-associated spatial transcriptomic signature by establishing an aging AAP mouse model and applying Visium spatial transcriptomics for understanding of the mechanisms in the context of the pancreatic tissue. Upon alcohol diet feeding and caerulein treatment, aging mice (18 months) developed significantly more severe AAP with 5.0-fold increase of injury score and 2.4-fold increase of amylase compared to young mice (3 months). Via Visium spatial transcriptomics, eight distinct tissue clusters were revealed from aggregated transcriptomes of aging and young AAP mice: five acinar, two stromal, and one islet, which were then merged into three clusters: acinar, stromal, and islet for the comparative analysis. Compared to young AAP mice, > 1300 differentially expressed genes (DEGs) and approximately 3000 differentially regulated pathways were identified in aging AAP mice. The top five DEGs upregulated in aging AAP mice include Mmp8, Ppbp, Serpina3m, Cxcl13, and Hamp with heterogeneous distributions among the clusters. Taken together, this study demonstrates spatial heterogeneity of inflammatory processes in aging AAP mice, offering novel insights into the mechanisms and potential drivers for AAP development. KEY MESSAGES: Mechanisms regarding high mortality of AAP in aging remain undefined. An aging AAP mouse model was developed recapturing clinical exhibition in humans. Spatial transcriptomics identified contrasted DEGs in aging vs. young AAP mice. Top five DEGs were Mmp8, Ppbp, Serpina3m, Cxcl13, and Hamp in aging vs. young AAP mice. Our findings shed insights for identification of molecular drivers in aging AAP.