Colorectal cancer (CRC) is the third most prevalent form of cancer worldwide, with colorectal cancer liver metastases (CRLM) representing a principal cause of CRC-related mortality. However, a lack of molecular subgroups based on the differentiation states of diverse cell types in CRLM poses a significant barrier to progress in precision therapy. We integrated single-cell RNA sequencing (scRNA-seq, GSE178318) of paired CRLM tissues to define an epithelial cell fate gene signature. To evaluate the intrinsic “malignant seed” potential, this signature was projected onto a large-scale primary reference cohort (TCGA-COAD/READ, N = 433) using consensus clustering to establish the Malignant Development Signature of CRLM (MDSCRLM). Comprehensive multi-omics analyses—encompassing somatic mutations, copy number variations, tumor mutational burden (TMB), and ATAC-seq chromatin accessibility (N = 81)—alongside immune microenvironment deconvolutions and proteomic data integration were performed. The clinical relevance of the MDSCRLM model was externally validated using immunohistochemistry in an independent clinical cohort of 45 patients. Furthermore, the biological function of HSPA1A, a core marker, was experimentally verified through in vitro assays and in vivo metastasis models. The MDSCRLM system discriminates three distinctmetastatic risk trajectories: Cluster 1—Aggressive-Metastasis-Enhanced CRLM (AMECRLM), Cluster 2—Cell Cycle-Active CRLM (CCACRLM), and Cluster 3—Growth-Inhibited CRLM (GICRLM). Survival analyses in the primary reference cohort validated the biological plausibility and prognostic impact of this model, revealing that GICRLM is associated with the most favorable prognosis while AMECRLM confers the poorest outcome. Our findings delineate distinct patterns of cellular heterogeneity, genomic instability (TP53 mutations), and gene expression across CRLM developmental stages. Prognostic validation in the clinical cohort and functional validation demonstrating that HSPA1A knockout attenuates tumor invasion and metastasis robustly supported the robustness of the MDSCRLM risk stratification. We established a novel, clinically relevant CRLM risk stratification model with strong diagnostic and prognostic potential. By identifying pre-existing malignant features and stage-specific therapeutic vulnerabilities within the primary tumor, this model bridges the gap between biological discovery and precision medicine in advanced colorectal cancer.

Preoperative lymph node metastasis (LNM) risk stratification is crucial for selecting endoscopic resection or colectomy in T1 right-sided colon cancer (T1 RCC), yet validated tools integrating preoperative predictive indicators remain lacking. This retrospective study included 628 patients with T1 RCC. Single-predictor and multi-predictor logistic regression models identified independent preoperative predictors of LNM to construct a nomogram. Model performance was assessed using area under the curve (AUC) and calibration metrics. Six preoperative factors constituted independent predictors of LNM: age (OR = 0.92, 95

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.

AIM:The etiology of cardiac polyps remains debated. Previous studies have primarily relied on symptomatic and endoscopic findings, lacking objective evidence of gastroesophageal reflux. We aimed to investigate the relationship between pathologic acid exposure and cardiac polyps based on 24-hour multichannel intraluminal impedance-pH monitoring (24h MII-pH) and high-resolution esophageal manometry (HREM). METHODS:This retrospective cross-sectional study enrolled patients who underwent upper endoscopy, 24h MII-pH and HREM examination. Clinical, endoscopic, and physiological parameters were compared between cardiac polyp and control group. Logistic regression was used to analyze the association between acid exposure time and cardiac polyps. RESULTS:A total of 123 patients (37 in the polyp group, 86 in the control group) were included. Acid exposure time were significantly elevated, while lower esophageal sphincter resting pressure was lower in the polyp group. After adjusting for confounders, each 1% increase in acid exposure time was associated with a 25% higher risk of cardiac polyps. Patients with acid exposure time >6% had a 3.7-fold increased risk compared to those with acid exposure time <4%. Pathological acid exposure was associated with cardiac polyps in populations with low LES resting pressure and without H. pylori infection. CONCLUSION:This study is the first to objectively demonstrate an independent positive correlation between acid exposure time and cardiac polyps particularly in H. pylori-negative patients and those with esophageal motility disorders, but causal relationships cannot be established. These findings provide new insights into the pathogenesis of cardiac polyps and suggest a potential role for acid-suppressive therapy in selected patients.

Gasdermin D (GSDMD), an effector molecule of cell pyroptosis, is known to be activated in various cells during inflammation. However, the patterns of GSDMD activation in immune regulatory cells such as myeloid-derived suppressor cells (MDSCs) remain unclear. In this study, we found that neutrophils in colorectal cancer (CRC) tissues exhibited reduced GSDMD transcription, as evidenced by a single-cell RNA sequencing result. Consistent with this, cleaved GSDMD expression is negatively correlated with S100A8 in CRC tissues. Additionally, CD15+CD14-LOX1+ cells (G-MDSCs) from the peripheral blood of CRC patients exhibited a significant reduction in GSDMD activation. Mice with ubiquitous GSDMD deficiency bred in a clean environment exhibited a notable increase in G-MDSCs. These GSDMD-/- MDSCs enhanced immunosuppressive activity by both inhibiting effector T-cell activity and promoting regulatory T-cell induction. This enhancement was also observed in GSDMDflox/flox-S100A8Cre mice, in which GSDMD was specifically deleted in MDSCs. The tumor-promoting effects in the GSDMD-/- and GSDMDflox/flox-S100A8Cre mice were abrogated following MDSC depletion, as shown by the use of an anti-DR5 antibody. In the absence of GSDMD, G-MDSCs showed reduced inflammasome activation and decreased production of IL-1β and IL-18. Furthermore, a significant reduction in interferon-related factor 8/7 (IRF8/7) was observed in GSDMD-/- G-MDSCs via bulk RNA sequencing analysis. After treatment with LPS/nigericin, these cells maintained mitochondrial integrity, thus impairing the mtDNA release and the downstream cGAS/STING/TBK1/IRF8/7 signaling axis activation. Reduced IRF8/7 levels were responsible for increased differentiation of GSDMD-/- G-MDSCs. Finally, treatment with a GSDMD recombinant lentivirus injected into in situ tumors significantly inhibited tumor growth and reduced G-MDSC levels, suggesting that a GSDMD-based vaccine could simultaneously exert anti-carcinoma and anti-MDSC effects.

Introduction:Proton pump inhibitors (PPIs) are widely prescribed for gastrointestinal disorders and are often used empirically in patients with pancreatic disease, yet their long-term impact on pancreatic health remains unclear. We evaluated whether regular PPI use is associated with risks of acute pancreatitis (AP), chronic pancreatitis (CP), and pancreatic cancer (PC). Methods:We analyzed 489,394 UK Biobank participants aged 38-73 years, comparing regular PPI users with non-users and with histamine-2 receptor antagonist (H2RA) users as an active comparator. Associations with incident pancreatic outcomes were estimated using Cox regression models, landmark analysis, and propensity score matching, supplemented by multiple sensitivity analyses, including stratified/interaction analyses, E-values, time-varying exposure models with immortal-time correction, dfbeta residuals correction, stricter follow-up with Firth penalization, full-cohort multivariable modeling, and alternative matching (disease risk score 1:1, entropy balancing). Complementary in vivo experiments used a cerulein-induced acute pancreatitis mouse model to examine the effects of short- and long-term PPI administration on pancreatic inflammation and histopathology. Results:In primary analyses, regular PPI use showed a time-dependent association with acute pancreatitis. However, this association was not robust: multiple sensitivity analyses indicated instability of the finding. Experimental validation in mice demonstrated that neither short-term nor long-term PPI administration altered pancreatic inflammation or histopathological damage in the cerulein-induced model. Discussion:Integrating large-scale cohort data with experimental evidence, our findings suggest that regular PPI use does not meaningfully influence the risk of acute pancreatitis, chronic pancreatitis, or pancreatic cancer.

Kynureninase (KYNU), a key enzyme in the tryptophan-kynurenine metabolic pathway, has been increasingly recognized for its role in immune regulation and inflammation. However, its involvement in radiation-induced intestinal injury (RIII) has not been fully elucidated. In this study, we identified a significant upregulation of KYNU expression in the colonic tissues of mice with RIII using transcriptomic analysis and experimental validation. Functional assays demonstrated that KYNU knockdown in NCM460 human intestinal epithelial cells attenuated radiation-induced apoptosis and oxidative stress, while promoting cell proliferation. Mechanistically, RNA sequencing (RNA-seq) and pathway enrichment analyses revealed that KYNU regulates the mitogen-activated protein kinase (MAPK) signaling pathway, as KYNU silencing reduced the phosphorylation levels of key MAPK proteins (extracellular signal-regulated kinase [ERK], c-Jun N-terminal kinase [JNK], and p38) following irradiation. Importantly, pharmacological inhibition of KYNU using carbidopa (CBP) significantly mitigated radiation-induced epithelial injury in vitro. In the RIII mouse model, CBP administration (prevention and treatment) increased the number of crypts, improved intestinal epithelial structure, and maintained the integrity of the intestinal barrier. These findings demonstrate, that KYNU plays a critical role in the pathogenesis of RIII and that its inhibition confers protection against intestinal damage by suppressing MAPK-mediated inflammatory responses. Targeting KYNU may thus offer a promising therapeutic strategy for the prevention and treatment of RIII.

ObjectiveMany researches have demonstrated an association between intra-pancreatic fat deposition (IPFD) and several pancreatic pathological conditions, including pancreatitis, pancreatic cancer, and type 2 diabetes mellitus (T2DM). The aim of this study is to investigate the influence of pancreatic diseases on the accumulation of pancreatic fat, to further explore which kind of pancreatic disease is significant, and to find out the possible mediating factors.MethodsA cross-sectional study based on the UK Biobank (UKB) data categorized participants by pancreatic disease status and collated relevant information. IPFD was measured using MRI in combination with a deep learning-based organ segmentation model, nnUNet. Linear regression models and mediation analysis were employed to explore the association between pancreatic diseases and IPFD.ResultsAmong 61,088 participants, those with pancreatic diseases exhibited higher IPFD than those without (pancreatic endocrine diseases: 11.72% vs 7.94%, P<0.001; pancreatic exocrine diseases: 9.44% vs 8.03%, P<0.001). After adjusting for multiple variables, a positive association between pancreatic endocrine diseases (particularly T2DM) and IPFD persisted, but not for pancreatic exocrine diseases. Obesity and dyslipidemia partially explained the relationship between T2DM and IPFD.ConclusionPancreatic exocrine disorders are not associated with an increased risk of IPFD, whereas pancreatic endocrine disorders, particularly T2DM, may exhibit a positive relationship. However, the possibility of reverse causation cannot be discounted.

Neutrophil extracellular traps (NETs) are key factors mediating acute inflammatory injury. However, the underlying mechanisms and potential therapeutic targets remain unclear. Previous results suggest Src may be involved in regulating the NETs formation. Here, Src is found activated in the NETs model in vitro, in the murine- and human-derived neutrophils (acute pancreatitis and sepsis). Moreover, p-Src expression correlates with the clinical prognosis of acute pancreatitis and sepsis patients. Meanwhile, the inhibition of Src activity (gene silencing or inhibitors) inhibits NETs formation in vitro. Mechanistically, Src directly activates RAF1 by regulating phosphorylation at the Ser 621 site and mediates the RAF/MEK/ERK pathway, thereby affecting the intracellular ROS production. Alternatively, Src activates the RAF/MEK/ERK pathway by mediating PKC phosphorylation. In vivo, neutrophil Src - specific defect significantly reduces acute inflammatory response, organ damage, and the NETs formation in damaged tissue. Eventually, Src inhibitors are used and validated their pharmacological effects. These results identify Src as a key mediator in intracellular ROS production, NETs formation, and acute organ injury. Hence, Src inhibition may represent a promising therapeutic strategy for treating acute organ injury.

Background:The tetraspanin CD53 transmembrane protein is vital in immune cells like B cells and T cells, playing a crucial role in various inflammatory conditions. However, its involvement in neutrophils regarding inflammation remains uncertain. This study aims to examine the impact of CD53 on neutrophil extracellular traps (NETs) formation. Methods:Phorbol 12-myristate 13-acetate (PMA) was utilized to establish an in vitro classical NETs model to investigate the influence of CD53 on NETs formation and its regulatory mechanisms. Subsequently, the link between CD53 and acute pancreatitis (AP), a model of aseptic inflammatory responses connected to NETs, was verified. Peripheral blood neutrophils from clinical AP patients were collected to explore the role of CD53 in AP, while an AP mouse model induced by caerulein was employed to confirm the impact of CD53 inhibition on AP mice pancreatic tissue. Results:Our study has shown that CD53 is significantly elevated in in vitro NETs models and neutrophils from AP patients. The expression of CD53 is closely related to the clinical prognosis of AP patients. At the same time, CD53 neutralizing antibody (Anti-CD53) can significantly inhibit the formation of NETs in vitro, inflammatory injury in AP mice and the formation of NETs in damaged tissues. Mechanistically, CD53 can modulate the PI3K/AKT pathway and promote the formation of NETs. Finally, targeted regulation of CD53 can effectively reduce inflammatory injury and NETs formation in damaged tissues of AP mice. Conclusion:The results of this study mark the first confirmation that CD53 plays a crucial role in NETs formation. Targeting CD53 inhibition could potentially serve as a novel therapeutic approach for the treatment of AP.

BACKGROUND:Acute pancreatitis (AP) is an inflammatory disorder of pancreas, where the formation of neutrophil extracellular traps (NETs) plays a crucial role in its pathogenesis. This study examined the therapeutic effect of Phellodendrine (PHE), a Phellodendron-derived alkaloid, on AP by assessing NETs formation and underlying mechanisms. METHODS:Mouse bone marrow neutrophils were isolated and stimulated to form NETs in vitro to assess PHE's impact. A Caerulein-induced AP mouse model was developed to assess the in vivo efficacy of PHE. Network pharmacology and RNA-seq analysis were utilized to investigate the mechanisms through which PHE alleviates AP. The functional role of the identified target was verified using a p38 inhibitor. RESULTS:PHE markedly inhibited NETs formation and reactive oxygen species (ROS) generation in vitro. In vivo experiments further revealed PHE treatment alleviated pancreatic injury and inflammation, which was accompanied by reduced NETs formation and neutrophil infiltration in the mouse of AP. Mechanistically, PHE targeted the p38 MAPK pathway, suppressing its activation and the subsequent membrane translocation of p47phox. Furthermore, co-administration with a p38 inhibitor abolished the inhibitory effects of PHE on NETs formation and ROS production. CONCLUSION:PHE mitigates pancreatic injury and inflammation in AP through its inhibitory effect on NETs formation and ROS production, mediated by targeting the p38 MAPK-p47phox pathway. This indicates its potential as an innovative therapeutic agent for the treatment of AP.

INTRODUCTION:To investigate whether increased intrapancreatic fat deposition (IPFD) heightens the risk of diseases of the exocrine and endocrine pancreas. METHODS:A prospective cohort study was conducted using data from the UK Biobank. IPFD was quantified using MRI and a deep learning-based framework called nnUNet. The prevalence of fatty change of the pancreas (FP) was determined using sex- and age-specific thresholds. Associations between IPFD and pancreatic diseases were assessed with multivariate Cox-proportional hazard model adjusted for age, sex, ethnicity, body mass index, smoking and drinking status, central obesity, hypertension, dyslipidemia, liver fat content, and spleen fat content. RESULTS:Of the 42,599 participants included in the analysis, the prevalence of FP was 17.86%. Elevated IPFD levels were associated with an increased risk of acute pancreatitis (hazard ratio [HR] per 1 quintile change 1.513, 95% confidence interval [CI] 1.179-1.941), pancreatic cancer (HR per 1 quintile change 1.365, 95% CI 1.058-1.762) and diabetes mellitus (HR per 1 quintile change 1.221, 95% CI 1.132-1.318). FP was also associated with a higher risk of acute pancreatitis (HR 3.982, 95% CI 2.192-7.234), pancreatic cancer (HR 1.976, 95% CI 1.054-3.704), and diabetes mellitus (HR 1.337, 95% CI 1.122-1.593, P = 0.001). DISCUSSION:FP is a common pancreatic disorder. Fat in the pancreas is an independent risk factor for diseases of both the exocrine pancreas and endocrine pancreas.

The aging of pancreatic beta cells is closely associated with various diseases, such as impaired glucose tolerance, yet the underlying regulatory mechanisms remain unclear. In this study, we screened young and aged mouse pancreatic beta cells' high-throughput sequencing data from the GEO public database. Utilizing bioinformatics techniques, we identified the key regulatory factor YY1 in the aging process of pancreatic islets. We observed a significant decrease in the expression of YY1 in a D-gal-induced mouse model of pancreatic aging and an H2O2-induced MIN6 cell model of aging. Moreover, both vivo and vitro models, we found that the YY1 agonist eudesmin (EDN) improved glucose intolerance in mice, alleviated aging of pancreatic beta cells, and downregulated the expression of cell cycle protein P21. Mechanistically, we discovered that EDN inhibited the P38/JNK MAPK pathway in aging cells. In summary, our study confirms the regulatory role of the transcription factor YY1 in the aging process of pancreatic beta cells. This finding may provide a new approach for the clinical treatment of pancreatic aging-related diseases such as impaired glucose tolerance or diabetes.

Severe acute pancreatitis (SAP) is characterized by high mortality rates and various complications, including skeletal muscle atrophy, which significantly exacerbates its outcomes. Despite its clinical relevance, the mechanistic understanding of the relationship between skeletal muscle and the pancreas in SAP remains limited. Our study aimed to elucidate this “organ crosstalk” and its potential implications. We established an SAP mouse model through pancreatic duct ligation (PDL) and evaluated pancreatic necrosis, skeletal muscle atrophy, and myonectin expression levels. Recombinant myonectin protein was administered in vivo and in vitro to assess its effects on acinar cell necrosis. Mechanistic insights were gained through RNA-seq data analysis and experimental validation. Serum samples from AP patients and healthy controls were collected to investigate the correlation between serum myonectin levels and disease severity. The mouse model exhibited severe pancreatic necrosis, skeletal muscle atrophy, and elevated myonectin levels, with myonectin administration exacerbating model severity. We identified iron accumulation-induced ferroptosis as a key pathway contributing to myonectin-mediated acinar cell necrosis. A total of 22 healthy controls and 52 patients with varying degrees of AP were included in the serum samples and clinical data (36.5

ScopeNaringenin (NAR) possesses unique anti‐inflammatory, antiapoptosis effects and various bioactivities; however, its role against radiation‐induced intestinal injury (RIII) remains unclear. This study aims to investigate whether NAR has protective effects against radiation‐induced intestinal injury and the underlying mechanisms.Methods and resultsC57BL/6J mice are exposed to a single dose of 13 Gy X‐ray total abdominal irradiation (TAI), then gavaged with NAR for 7 days. NAR treatment prolongs the survival rate, protects crypts and villi from damage, alleviates the level of radiation‐induced inflammation, and mitigates intestinal barrier damage in the irradiated mice. Additionally, NAR reduces immune cell infiltration and intestinal epithelial cell apoptosis. NAR also shows radioprotective effects in human colon cancer cells (HCT116) and human intestinal epithelial cells (NCM460). It reduces cell damage by reducing intracellular calcium ion levels and reactive oxygen species (ROS) levels. NAR‐mediated radioprotection is associated with the downregulation of transient receptor potential vanilloid 6 (TRPV6), and inhibition of apoptosis pathway. Notably, treatment with NAR fails to further increase the protective effects of the TRPV6 inhibitor 2‐APB, indicating that TRPV6 inhibition is essential for NAR activity.ConclusionNAR inhibits the apoptosis pathway by downregulating TRPV6 and reducing calcium ion level, thereby alleviating RIII. Therefore, NAR is a promising therapeutic drug for RIII.

Efferocytosis, the clearance of apoptotic cells by macrophages, plays a crucial role in inflammatory responses and effectively prevents secondary necrosis. However, the mechanisms underlying efferocytosis in acute pancreatitis (AP) remain unclear. In this study, we demonstrated the presence of efferocytosis in injured human and mouse pancreatic tissues. We also observed significant upregulation of CD47, an efferocytosis-related the "do not eat me" molecule in injured acinar cells. Subsequently, we used CRISPR-Cas9 gene editing, anti-adeno-associated virus (AAV) gene modification, and anti-CD47 antibody to investigate the potential therapeutic role of AP. CD47 expression was negatively regulated by upstream miR133a, which is controlled by the transcription factor TRIM28. To further investigate the regulation of efferocytosis and reduction of pancreatic necrosis in AP, we used miR-133a-agomir and pancreas-specific AAV-shTRIM28 to modulate CD47 expression. Our findings confirmed that CD47-mediated efferocytosis is critical for preventing pancreatic necrosis and suggest that targeting the TRIM28-miR133a-CD47 axis is clinically relevant for the treatment of AP.

Objective:This study aimed to evaluate the effectiveness of an Objectives and Key Results (OKR)-based nursing intervention in enhancing the quality of bowel preparation for colonoscopy. Methods:Between July and December 2021, 180 inpatients who attended the Department of Gastroenterology, Dongtai Hospital, Nantong University, had their first colonoscopy and were able to complete bowel preparation and perform colonoscopy, and met the inclusion criteria of this study, were selected as study subjects. The 180 inpatients were divided into a control group (n=90, receiving conventional care) and a research group (n=90, managed with specialist care quality standards in addition to conventional care) using a random number table to compare the pass rate of bowel preparation cecum insertion rate, compliance rate, patient satisfaction and incidence of adverse reactions. Results:The research group had higher rates of successful bowel preparation, appendiceal intubation, adenoma detection, compliance, and patient satisfaction than the control group (P < .05). The incidence of adverse reactions in the research group was lower than in the control group (P < .05). Conclusion:Implementing OKR-based nursing interventions in bowel preparation protocols significantly enhances patient outcomes and satisfaction, suggesting its widespread adoption in gastroenterology practices.