Dysregulated cholesterol metabolism is a recognized metabolic hallmark of cancer. While the transcription factor SREBP2 is a master regulator of this pathway, how its activation converts metabolic stress into the development of carcinogenic signals in colorectal cancer (CRC) remains unclear. Through clinical and preclinical analyses, we first confirmed that hypercholesterolemia and elevated tumoral SREBP2 are hallmarks of CRC. Using multi-omics integration, we identified CNPY3 as a direct transcriptional target of SREBP2. Functionally, CNPY3 drives CRC cell proliferation, invasion, and tumor growth via a cholesterol synthesis-independent oncogenic program. Clinically, high CNPY3 expression robustly correlated with advanced disease and poor patient survival. Mechanistically, we discovered that CNPY3 undergoes liquid-liquid phase separation (LLPS), a property dependent on its intrinsically disordered C-terminal region. This LLPS capacity is essential for its oncogenic function, as it enables CNPY3 to enhance MDM2 phosphorylation at the activating Ser166 site and promote its nuclear translocation. Consequently, CNPY3 potentiates MDM2-mediated ubiquitination and degradation of the tumor suppressor p53. Genetic ablation of p53 completely abolished the pro-tumorigenic effects of CNPY3, confirming p53 as the critical downstream effector. Crucially, this axis specifically targets wild-type p53, having no effect on common p53 mutants. Pharmacological disruption of the MDM2-p53 interaction with Nutlin-3 effectively reversed CNPY3-driven malignancy both in vitro and in vivo. Our work unveils a SREBP2-CNPY3-MDM2-p53 signaling axis that links cholesterol metabolic dysregulation to p53 pathway inactivation in CRC. We further established that the oncogenic activity of CNPY3 is mediated through its biophysical property of LLPS. These findings nominate CNPY3 as a novel prognostic biomarker and a compelling therapeutic target for p53-wild-type CRC.

Background and Objectives: Despite surgical intervention for remission, recurrence is nearly inevitable in patients with Crohn's disease (CD). While several maintenance therapies are available, the optimal strategy for preventing postoperative recurrence remains uncertain. Materials and Methods: This systematic review and network meta-analysis included placebo-controlled or head-to-head randomized controlled trials (RCTs) from MEDLINE, Embase, and Cochrane Central up to 4 July 2024. Studies assessed maintenance therapies for CD after curative resection. Data were extracted from intention-to-treat (ITT) and per-protocol (PP) analyses separately. The primary outcomes were endoscopic and clinical relapse. A Bayesian network meta-analysis provided risk ratios (RRs) and 95% confidence intervals (CIs). This study is registered with PROSPERO (CRD42024629013). Results: From 1492 screened records, 45 randomized controlled trials met the inclusion criteria. Compared with placebo, clinically significant prevention of clinical recurrence was achieved with adalimumab (RR = 0.17; GRADE High), nitroimidazoles (RR = 0.35; High), infliximab (RR = 0.59; Moderate), thiopurine analogs (RR = 0.41; Moderate), and high-dose mesalamine (RR = 0.74; High), while azathioprine-metronidazole combination therapy demonstrated superior efficacy to azathioprine monotherapy. For endoscopic recurrence mitigation, therapeutic efficacy was confirmed for adalimumab (RR = 0.24; Low), infliximab (RR = 0.32; Moderate), vedolizumab (RR = 0.36; Low), and thiopurine analogs (RR = 0.64; Moderate). Conclusions: This network meta-analysis establishes pharmacological hierarchies for preventing postoperative Crohn's disease recurrence. Adalimumab is the most effective monotherapy for clinical recurrence prevention, while combination therapies of adalimumab/azathioprine plus nitroimidazole show superior efficacy. For endoscopic recurrence prevention, adalimumab also ranks as the most effective intervention. These findings guide therapy selection but require validation for newer agents through randomized trials.

BACKGROUND:Emerging evidence suggests that dual targeted therapy (DTT), which employs two biologics or small molecules concurrently, may improve outcomes for patients with refractory inflammatory bowel disease (IBD). We conducted a systematic review and meta-analysis to assess the efficacy and safety of DTT, with a comparative evaluation of different combination therapies. METHODS:We systematically searched MEDLINE, Embase, Cochrane Library, CBM, CNKI, VIP, and WanFang from inception to March 8, 2026. Eligible studies were clinical trials or cohort studies reporting DTT outcomes in IBD. Efficacy outcomes included clinical response, clinical remission, clinical improvement, and endoscopic improvement; safety outcomes included adverse events (AEs) and serious adverse events (SAEs). RESULTS:Sixty-three studies comprising 2097 patients were included. Overall, DTT exhibited promising efficacy in refractory IBD, with pooled clinical response and remission rates of 68.0% (95% confidence interval [CI], 62.7%-72.8%) and 50.7% (95% CI, 44.2%-57.1%), respectively. Antitumor necrosis factor α (TNFα) plus IL-12/23 inhibitors was associated with higher clinical improvement than anti-TNFα plus anti-integrin therapy (odds ratio [OR] = 4.74; 95% CI, 2.31-9.73) and anti-integrin plus Janus kinase inhibitors (OR = 17.52; 95% CI, 1.09-281.12) in IBD patients. The safety profile of DTT was acceptable, with pooled rates of AEs and SAEs being 28.2% (95% CI, 21.9%-35.5%) and 8.3% (95% CI, 6.3%-10.8%), respectively. Notably, anti-integrin plus IL-12/23 inhibitors showed lower AE rates than anti-TNFα plus IL-12/23 inhibitors (OR = 0.19; 95% CI, 0.06-0.65). CONCLUSIONS:DTT shows promising efficacy with an acceptable safety profile in refractory IBD. Large-scale, high-quality studies are required to validate these findings.

Background:The incidence of cytomegalovirus (CMV) infection is increasing. This study explored the clinical characteristics, diagnosis, treatments, and prognosis of gastric lesions caused by CMV infection. Methods:This is a systematic review of the literature on CMV infection involving the stomach. Results:A total of 39 English publications reporting 44 cases of CMV gastritis were identified through literature retrieval. Clinically, patients with CMV gastritis commonly presented with gastrointestinal symptoms, including abdominal pain, nausea and/or vomiting, and gastrointestinal bleeding. Endoscopic findings most frequently included mucosal ulcers (54.55%), erosions (27.27%), and erythema (20.45%). Most patients had a history of immunosuppression, such as AIDS, postorgan transplantation, cancer chemotherapy, or long-term use of corticosteroids and immunosuppressants. The diagnosis was primarily confirmed by endoscopic biopsy combined with CMV DNA quantitative testing. The majority of patients improved after antiviral therapy, while a small subset experienced spontaneous resolution. However, a few cases (2.27%) progressed to gastric cancer, and some (4.55%) resulted in death. Conclusion:In patients with a history of immunosuppression presenting with gastrointestinal symptoms such as abdominal pain, nausea, vomiting, or gastrointestinal bleeding, CMV gastritis should be considered in the differential diagnosis. Endoscopic biopsy with histopathological examination plays a crucial role in confirming the diagnosis.

Background:Ulcerative colitis (UC) is often accompanied by depressive symptoms, yet the association between disease activity and depression remains insufficiently characterized. Objective:To evaluate the correlations between SCCAI scores, Mayo endoscopic severity scores, and QIDS-SR16 depression scores in patients with UC. Methods:This cross-sectional study included 106 hospitalized UC patients from January 2023 to December 2024. Disease activity was assessed using the Simple Clinical Colitis Activity Index (SCCAI), and endoscopic severity was assessed with the Mayo score in a subsample (n = 54). Depressive symptoms were evaluated using QIDS-SR16. Multivariable linear regression and restricted cubic spline models were applied to examine linear and nonlinear associations. Results:A 1-point increase in SCCAI score was associated with a 0.41-point increase in QIDS-SR16 score (β = 0.41, 95% CI: 0.19-0.63, P < 0.001). A 1-point increase in the Mayo score corresponded to a 1.07-point increase in QIDS-SR16 (β = 1.07, 95% CI: 0.24-1.90, P = 0.015). Restricted cubic spline analysis revealed a nonlinear association between SCCAI and QIDS-SR16, with greater sensitivity of depressive symptoms at lower SCCAI levels. Conclusion:In this cross-sectional real-world study, both clinical disease activity (SCCAI) and endoscopic severity (Mayo score) were independently and positively correlated with depressive symptom burden in UC patients. These findings support incorporating routine depression screening into UC clinical management to facilitate timely detection and intervention.

BACKGROUND & AIMS:Approximately 25.2% of patients with inflammatory bowel disease (IBD) suffer from psychological disorders, particularly depression. Recent studies have indicated a close relationship between intestinal immunity and brain disorders. METHODS:We performed transcriptome analysis and immunofluorescence staining of colonic samples from patients with IBD. The role of perforin generated by colonic CD8+ T cells in IBD-induced depression was investigated in dextran sulfate sodium- and CD8+ T-cell transfer-induced colitis by using Prf1-EGFP reporter and Prf1 knockout mice. RESULTS:In this study, we revealed a significant correlation between depressive symptom severity and perforin production in CD8+ T cells in both patients with IBD and mice with colitis. Moreover, perforin deficiency in CD8+ T cells mitigated both inflammation and depressive-like behaviors in mice with colitis. Mechanistically, perforin and granzyme B were found to stimulate the expression of CXCL9 in colonic epithelial cells. CXCL9 was shown to be released into the circulation and to enter the hippocampus, where it induced endoplasmic reticulum stress in hippocampal neurons through the CXCR3-HSPA5 axis. This cascade of events subsequently was found to exacerbate depression. Neutralizing CXCL9 in vivo alleviated depression but had no effect on colitis in mice. CONCLUSIONS:Perforin generated by colonic CD8+ T cells promotes intestinal epithelial cell CXCL9 production, which leads to neuronal endoplasmic reticulum stress in hippocampus and induces depression in IBD.

INTRODUCTION:X842 is a new type of gastric acid-suppressing agent with a rapid onset of action and a long duration of effect. We aim to investigate the efficacy and safety of different doses of X842 vs lansoprazole in the treatment of patients with erosive esophagitis (EE). METHODS:This phase 2 study included 90 patients with EE (Los Angeles grades A-D) who were randomized (1:1:1) to receive oral low-dose X842 (50 mg/d, n = 31), high-dose X842 (100 mg/d, n = 31), or lansoprazole (30 mg/d, n = 30) for 4 weeks. The main efficacy end point was the EE healing rate, which was the proportion of patients who achieved endoscopic healing after 4 weeks of treatment. RESULTS:For intention-to-treat analysis, the EE healing rates at 4 weeks were 93.6% (29/31), 79.3% (23/29), and 80.0% (24/30) for the X842 50 mg, the X842 100 mg, and the lansoprazole 30 mg groups. For per-protocol analysis, the EE healing rates at 4 weeks were 93.6% (29/31), 80.8% (21/26), and 82.1% (23/28) in the 3 groups, respectively. The EE healing rate did not significantly differ among the 3 groups in either the intention-to-treat ( P = 0.2351) or per-protocol ( P = 0.3320) analysis. The incidence of drug-related treatment-emergent adverse events did not differ among groups. No severe drug-related treatment-emergent adverse events occurred in the X842 group. DISCUSSION:Our findings confirmed that X842 had efficacy and a favorable safety profile similar to those of lansoprazole. Therefore, X842, a novel potassium-competitive acid blocker, is expected to become a promising therapeutic agent for EE.

Background:The etiology and pathogenesis of inflammatory bowel disease (IBD) are generally thought to be related to immune dysfunction and intestinal microbiota dysbiosis. However, the exact mechanisms remain unclear. Methods:We applied a DSS-induced colitis model in wild-type and perforin-deficient (Prf1-/- ) mice. Adoptive transfer experiments and metabolic profiling were conducted, and 16S rRNA gene sequencing analyzed gut microbiota. The impact of a 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) inhibitor on inflammation and dysbiosis was also assessed. Results:In this study, we demonstrated that perforin production in CD8+ T cells was significantly increased in both patients with IBD and mice with colitis. Moreover, compared with wild-type mice, perforin deficiency (Prf1-/- ) mice exhibited mitigated inflammation in a DSS-induced colitis model. The CD8+ T cell adoptive transfer model indicated that perforin produced by CD8+ T cells directly induced colitis. Prf1-/- mice with colitis exhibited activation of the fatty acid metabolic process, highlighted by increased expression of Hmgcs2 and pyruvate dehydrogenase kinase isoform 4 (Pdk4) in the colon and accumulation of the related metabolite β-hydroxybutyrate. The absence of perforin partly reversed the imbalance in the gut microbiota composition caused by DSS, including increases in Alloprevotella and Parabacteroides. However, the HMGCS2 inhibitor exacerbated intestinal inflammation and dysbiosis in Prf1-/- mice. Conclusion:CD8+ T cell-derived perforin promoted colitis by disrupting gut microbiota composition through the suppression of β-hydroxybutyrate production. This study provides novel targets for therapeutic strategies of IBD.

Immunoglobulin G4 (IgG4)-related pancreatobiliary disease typically manifests as obstructive jaundice, complicating therapeutic choices. Glucocorticoids (GCs) are the primary treatment with many challenges, including high recurrence rates and patient tolerance variability. Endoscopic biliary drainage (EBD) is used to alleviate obstruction, but its role during treatment in IgG4-related pancreatobiliary disease is still contested. There remains a paucity of research comparing the potential benefits of combination therapy with GCs and EBD versus GCs monotherapy. This retrospective study divided 55 IgG4-related pancreatobiliary disease patients into two groups: GCs and GCs + EBD groups. We collected clinical data at the 1st, 3rd, 6th, and 12th months post-treatment to compare treatment efficacy, complication rates, and recurrence. Furthermore, logistic regression was used to analyze independent risk factors for recurrence. The results demonstrated that both treatment regimens significantly reduced total bilirubin (TBIL) and IgG4 levels within one year. The common bile duct diameter significantly decreased at the 6th and 12th months post-treatment compared to baseline. Except for significantly greater TBIL improvement in the GCs+EBD group at the 12th month, no other statistically significant differences were observed between groups. No statistically significant difference was observed in the cumulative recurrence rate within one year after treatment between the GCs and GCs+EBD groups. Finally, we identified elevated baseline IgG4 levels as an independent risk factor for post-treatment recurrence. The combination therapy of GCs and EBD did not exhibit significant differences in immunologic remission, complication rates, or recurrence compared with GCs monotherapy for IgG4-related pancreatobiliary disease. Nonetheless, EBD showed certain benefits in alleviating biliary obstruction.

OBJECTIVE:The objective of this study is to compare the efficacy and safety of lubiprostone (Lub) with osmotic laxatives in the treatment of chronic idiopathic constipation (CIC). METHODS:A comprehensive literature search was conducted using PubMed, EMBASE, and the Cochrane Library in May 2024. Studies that met the inclusion criteria were manually searched by two independent reviewers. The efficacy was assessed by the proportion of patients with spontaneous bowel movements (SBMs) within 24 h after the first administration of the medication and SBMs in Weeks 1 and 4. Safety was evaluated based on adverse events including nausea, diarrhea, and abdominal distension. Optimal probability values and the surface under the cumulative ranking area (SUCRA) were also calculated for all interventions. Higher SUCRA values indicate better efficacy and safety of the intervention. RESULTS:Following a thorough search and screening process, 25 articles were included. Among the selected trials, 8 compared Lub to placebo, 10 compared polyethylene glycol (PEG) to placebo, 4 compared lactulose (Lac) to placebo, and 3 compared PEG to Lac. The meta-analysis results indicated that Lub and osmotic laxatives were significantly more effective than placebo. According to the SUCRA results, the highest rank probabilities were for Lub in increasing the SBMs and reducing abdominal distension. CONCLUSION:Lubiprostone is more effective than PEG and Lactulose for treating CIC, with comparable safety profiles. However, this conclusion requires further validation through large-scale, high-quality studies.

Background Crohn’s disease (CD) is marked by disruption of intestinal epithelial barrier, with unclear underlying molecular mechanisms. This study aimed to investigate key genes regulating the intestinal barrier in CD patients. Methods Differential gene expression analysis and gene set enrichment analysis were conducted to identify potential key genes involved in CD within the GEO database. Single-cell RNA sequencing from ileum samples in GSE134809 of 59,831 inflamed and uninflamed cells from 11CD patients and microarray data from ileal tissues in GSE69762 (3 controls and 4CD patients) and GSE75214 (11 controls and 51CD patients) with GSE179285 (49 uninflamed and 33 inflamed from CD patients) as the validation set. Protein-protein interaction and logistic regression analyses identified key downregulated genes in CD. A key gene was then investigated through immunohistochemistry of ileal tissues from 5CD patients and in the Caco-2 cell line with RNA interference and treatment with IFN-γ and TNF-α to stimulate inflammation. Results Single-cell RNA-seq identified 33 genes and microarray identified 167 genes with significant downregulation in inflamed CD samples. PCK1 was identified and validated as one of the most promising candidate genes. Reduced PCK1 expression was evident in inflamed ileal tissues. In vitro, knockdown of PCK1 resulted in decreased cell viability, increased apoptosis, and reduced nectin-2 production, while combination of IFN-γ and TNF-α significantly reduced PCK1. Conclusions PCK1 is downregulated in inflamed ileal tissues of CD patients and may be a key factor in maintaining epithelial integrity during inflammation in Crohn’s disease.

Inflammatory bowel disease (IBD) is a chronic, relapsing condition wherein biologics have improved disease prognosis but introduced elevated infection susceptibility. Vedolizumab (VDZ) demonstrates unique safety advantages; however, a comprehensive systematic comparison regarding the risk of Clostridioides difficile infection (CDI) between vedolizumab and alternative medications remains absent. Medline, Embase, Cochrane, and clinicaltrials.gov registry were comprehensively searched. Pooled estimates of CDI proportion, incidence, pooled risk ratio between ulcerative colitis (UC) and Crohn’s disease (CD), vedolizumab and other medications were calculated. Data synthesis was completed in R using the package “meta”. Of the 338 studies initially identified, 30 met the inclusion/exclusion criteria. For CDI risk, the pooled proportion was 0.013 (95

ObjectiveTegoprazan represents a newly developed potassium-competitive acid blocker utilized for the treatment of acid-related disorders. The present study aimed to explore the therapeutic effectiveness of tegoprazan in Chinese individuals with duodenal ulcers (DU).MethodsIn the current multicenter, randomized, double-blind, double-dummy, parallel-group, non-inferiority, phase III clinical trial, individuals with DU underwent randomization 1:1 to be administered tegoprazan 50 mg or lansoprazole 30 mg once daily. The primary efficacy endpoint was the 6-week cumulative endoscopic ulcer healing rate. Secondary endpoints included 4-week endoscopic ulcer healing rate and relief of DU-related gastrointestinal symptoms at weeks 2, 4, and 6. Safety analysis encompassed adverse events (AEs) and laboratory indexes.ResultsThe 6-week cumulative endoscopic ulcer healing rates were 96.9% (188/194) and 99.0% (189/191) in the tegoprazan and lansoprazole groups, respectively, indicating a difference of -2.0% (95% confidence interval (CI) = -4.9 to 0.8) in the full analysis set (FAS). The corresponding healing rates were 98.4% (185/188) and 99.5% (183/184) in the per-protocol set, respectively, indicating a difference of -1.1% (95% CI = -3.1 to 1.0). The 4-week healing rates in the tegoprazan and lansoprazole groups were 89.2% (173/194) and 88.5% (169/191) in the FAS, respectively, with a difference of 0.7% (95% CI = -5.6 to 7.0). Treatment-related AEs, all mild-to-moderate, were reported in 38.2% (78/204) and 48.2% (94/195) of participants in the tegoprazan and lansoprazole groups, respectively.ConclusionsTegoprazan 50 mg once daily is effective and non-inferior to lansoprazole 30 mg once daily in Chinese patients with DU, showing a promising safety and tolerability profile.ClinicalTrials.gov registration numberNCT05010954.

Objective:To analyze the clinicopathological features of de novo early colorectal cancer and to evaluate the efficacy of endoscopic treatment.Methods:Patients with de novo early colorectal cancer who underwent endoscopic resection in Beijing Friendship Hospital, Capital Medical University from June 2020 to May 2022 were enrolled. The baseline data, endoscopic manifestations, treatment methods, postoperative pathological results and prognosis of the patients were collected retrospectively.Results:A total of 33 patients with de novo early colorectal cancer were enrolled with the age of 62.67 ± 8.62 years, and the male to female ratio was 7.25∶1. The long diameter of lesions was 0.96 ± 0.36 cm. The lesion morphology was mainly superficial phenotype (type 0-Ⅱ), accounting for 72.7% (24/33). Endoscopic submucosal dissection (ESD) was performed in 29 cases and endoscopic mucosal resection (EMR) was performed in 4 cases. Postoperative pathology showed that 11 cases (33.3%) were well differentiated tubular adenocarcinoma, of which the superficial submucosal layer was invaded in 2 cases. Twenty cases (60.6%) were moderately differentiated tubular adenocarcinoma, of which the superficial submucosa layer was invaded in 5 cases and the deep submucosa layer in 15 cases. Two cases (6.1%) were moderately-poorly differentiated tubular adenocarcinoma, where the deep submucosa layer was invaded in both. There was significant correlation between the depth of invasion and the degree of differentiation ( P<0.001), and moderately and moderately-poorly differentiated lesions were more likely to invade the deep submucosa layer. The en bloc resection rate was 100.0% (33/33), the complete resection rate was 97.0% (32/33), and the curative resection rate was 42.4% (14/33). Among the 19 patients who did not achieve curative resection, 13 patients received supplementary surgical treatment. No tumor residue or lymph node metastasis was found in the postoperative pathology. All patients were followed up for 3-25 months, and no signs of local recurrence or metastasis were found. Conclusion:Most de novo early colorectal cancers are superficial phenotype under endoscopy. The pathology is mainly moderately differentiated tubular adenocarcinoma. Endoscopic resection of de novo early colorectal cancer shows encouraging short-term efficacy.

Objective:To investigate the clinical features, characteristics under white-light endoscopy and endoscopic ultrasonography, and treatment strategies of gastritis cystica profunda (GCP) accompanied with or without neoplastic lesions.Methods:Clinical data of 35 patients, who were pathologically diagnosed as having GCP after endoscopic or surgical resection in Beijing Friendship Hospital, Capital Medical University from January 2015 to February 2021, were retrospectively collected, including 27 patients with neoplastic lesions. The demographic information, clinical manifestations, endoscopic features, treatment methods, and pathological results of GCP were summarized.Results:Thirty-five patients with GCP were 68.26±8.08 years old, and mostly male (80.00%, 28/35). The most common symptom was upper abdominal pain, accounting for 31.43% (11/35), and 25.71% (9/35) had no symptoms. Other symptoms included acid reflux, heartburn, abdominal distension, anemia, and choking sensation after eating. The most common site of GCP was cardia (51.43%, 18/35), and the main endoscopic manifestations of GCP were flat mucosal lesions (68.57%, 24/35), mainly 0-Ⅱa and 0-Ⅱa+Ⅱc type lesions, accounting for 66.67% (16/24). The second common endoscopic manifestation was polypoid eminence (20.00%, 7/35). Endoscopic ultrasonography was performed in 15 patients, with main manifestations of uniform hypoechoic with or without cystic echo (73.33%, 11/15). Among the GCP cases, 33 patients received endoscopic resection, and 2 received surgical treatment. The treatment processes were all successfully completed, and en-bloc resection was accomplished for all lesions receiving endoscopy, with the mean endoscopic operation time of 86.13 min. One patient suffered postoperative delayed bleeding after ESD which was stopped by endoscopic hemostasis. Final pathological results showed that the proportion of GCP complicated with neoplastic lesions was 77.14% (27/35), 68.57% (24/35) with early gastric cancer or precursor. Twenty-three cases achieved R0 resection. One case showed positive basal resection margin and vascular invasion, and recurrence happened in situ at the 5th month of follow-up, surgical resection was then performed. The endoscopic complete resection rate was 95.83% (23/24).Conclusion:GCP usually occurs in middle-aged and elderly male, often located in cardia, manifested mainly as flat mucosal lesions and polypoid changes. Endoscopic ultrasonography shows a high diagnostic value for GCP, and endoscopic treatment is safe and effective minimally invasive treatment for GCP.