Liver fibrosis shows limited treatment efficacy, driven by metabolic reprogramming and epigenetics, while the role of lactate-mediated lactylation in hepatic microenvironment remains unclear. Here, through integrative analysis of public databases and human cirrhotic liver tissues, we identified a pathogenic FSP1+ (fibroblast specific protein 1) macrophage subset as a key therapeutic target. We uncovered a novel FSP1-glycolysis-lactylation axis that drives fibrotic progression through metabolic-immune crosstalk. Expanded FSP1+ macrophage infiltration was observed in human cirrhotic liver tissues and myeloid-specific Fsp1 knockout markedly attenuates inflammation and fibrosis. Mechanistic investigations reveal that FSP1 physically interacts with pyruvate kinase M2 (PKM2) in macrophages, inhibiting its ubiquitin-proteasome degradation to stabilize the enzyme. This FSP1-PKM2 interaction enhances glycolytic flux and lactate production, which in turn promotes KAT2B-dependent lactylation of phosphoglycerate kinase 1 (PGK1) at lysine 353 (K353). The posttranslational modification creates a positive feedback loop by concurrently activating PGK1 and pyruvate dehydrogenase kinase 1, which blocks mitochondrial pyruvate metabolism, thereby amplifying glycolysis and PGK1 lactylation. Notably, we developed a cell-penetrating peptide targeting PGK1-K353 lactylation that effectively attenuates the progression of liver fibrosis. Our findings establish lactate-mediated lactylation of PGK1 as a critical node in fibrotic metabolism and reveal a previously unrecognized FSP1-glycolysis axis that sustains the pro-fibrotic microenvironment. Targeting PGK1-K353 lactylation represents a promising therapeutic strategy for chronic liver diseases.

OBJECTIVES:Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a major global health burden, yet its underlying mechanisms remain incompletely defined. We aimed to investigate the role of intestinal NOD-, LRR-, and pyrin-domain-containing protein 3 (NLRP3) inflammasome in the gut-liver axis to identify potential therapeutic targets for MASLD. METHODS:Eight-week-old male mice were given a methionine-choline-deficient (MCD) diet for 4 weeks to induce MASLD-associated fibrosis. The functional role of NLRP3 was assessed using Vil1creNlrp3f/f mice with intestinal epithelial cell-specific Nlrp3 deletion. To evaluate the potential influence of the gut microbiota, Vil1creNlrp3f/f-MCD mice were co-housed with Nlrp3f/f-MCD counterparts. The effect of butyrate was also evaluated in Vil1creNlrp3f/f-MCD mice via oral gavage for 3 weeks. The role of intestinal NLRP3 was further validated in a carbon tetrachloride (CCl4)-induced liver fibrosis model. RESULTS:Intestinal NLRP3 expression was markedly reduced in wild-type mice given MCD diet. Compared with Nlrp3f/f-MCD mice, Vil1creNlrp3f/f-MCD mice developed more severe MASLD and exhibited impaired intestinal barrier integrity, whereas the co-housing condition alleviated hepatic pathology. Moreover, butyrate administration significantly improved hepatic steatosis and fibrosis in Vil1creNlrp3f/f-MCD mice. Mechanistic analysis revealed attenuated hepatic peroxisome proliferator-activated receptor α (PPARα) activation and enhanced hepatic activator protein (AP)-1 signaling in Vil1creNlrp3f/f-MCD mice, both of which improved under co-housing condition or butyrate treatment. Similarly, intestinal Nlrp3 deletion aggravated CCl4-induced liver fibrosis. CONCLUSION:Loss of intestinal Nlrp3 diminished butyrate production, inhibited PPARα expression, and enhanced AP-1 signaling, collectively intensifying MASLD progression.

Metabolic dysfunction–associated steatotic liver disease (MASLD) represents a major global health burden, yet its underlying mechanisms remain incompletely defined. We aimed to investigate the role of intestinal NOD-, LRR-, and pyrin-domain-containing protein 3 (NLRP3) inflammasome in the gut–liver axis to identify potential therapeutic targets for MASLD. Eight-week-old male mice were given a methionine-choline-deficient (MCD) diet for 4 weeks to induce MASLD-associated fibrosis. The functional role of NLRP3 was assessed using Vil1 cre Nlrp3 f/f mice with intestinal epithelial cell-specific Nlrp3 deletion. To evaluate the potential influence of the gut microbiota, Vil1 cre Nlrp3 f/f -MCD mice were co-housed with Nlrp3 f/f -MCD counterparts. The effect of butyrate was also evaluated in Vil1 cre Nlrp3 f/f -MCD mice via oral gavage for 3 weeks. The role of intestinal NLRP3 was further validated in a carbon tetrachloride (CCl 4 )-induced liver fibrosis model. Intestinal NLRP3 expression was markedly reduced in wild-type mice given MCD diet. Compared with Nlrp3 f/f -MCD mice, Vil1 cre Nlrp3 f/f -MCD mice developed more severe MASLD and exhibited impaired intestinal barrier integrity, whereas the co-housing condition alleviated hepatic pathology. Moreover, butyrate administration significantly improved hepatic steatosis and fibrosis in Vil1 cre Nlrp3 f/f -MCD mice. Mechanistic analysis revealed attenuated hepatic peroxisome proliferator-activated receptor α (PPARα) activation and enhanced hepatic activator protein (AP)-1 signaling in Vil1 cre Nlrp3 f/f -MCD mice, both of which improved under co-housing condition or butyrate treatment. Similarly, intestinal Nlrp3 deletion aggravated CCl 4 -induced liver fibrosis. Loss of intestinal Nlrp3 diminished butyrate production, inhibited PPARα expression, and enhanced AP-1 signaling, collectively intensifying MASLD progression.

Introduction: and objectives: Extracellular vesicles (EVs) have emerged as key players in intercellular communication within the context of non-alcoholic fatty liver disease (NAFLD). This study aims to explore the intricate crosstalk between hepatocytes and hepatic stellate cells (HSCs) mediated by EVs in NAFLD. Materials and methods: EVs ferritin was detected in hepatocytes stimulated with free fatty acids (FFA) as well as in NAFLD mice. Deferoxamine (DFO) was employed to reduce ferritin levels, while GW4869 was utilized to inhibit EVs. The impact of EVs ferritin on the HSCs activation was evaluated both in vitro and in vivo. Additionally, serum EVs ferritin levels were compared between NAFLD patients and controls. Results: FFA treatment induces the formation and secretion of EVs and facilitates the release of ferritin from hepatocytes via EVs. Subsequently, EVs ferritin is hijacked by HSCs, prompting accelerated HSCs activation. Silencing ferritin with DFO and inhibiting EVs formation and secretion with GW4869 can reverse the effects of FFA treatment and disrupt the communication between hepatocytes and HSCs. Accumulation of ferritin leads to excessive reactive oxygen species (ROS) production, promoting HSCs fibrogenesis. Conversely, depleting EVs ferritin cargo restores liver function, concurrently mitigating NAFLD-associated fibrosis. Notably, NAFLD patients exhibit significantly elevated levels of serum EVs ferritin. Conclusions: This study unveils a previously underestimated role of ferritin in HSCs upon its release from hepatocytes, emphasizing DFO as a promising compound to impede NAFLD advancement.

In recent years, there has been a trend towards of over-diagnosis in inflammatory bowel disease(IBD). Over-diagnosis, like under-diagnosis, also triggers endless consequences.In the clinical practice, most of the effort is focused on distinguishing IBD from the common diseases such as intestinal tuberculosis, intestinal Behcet′s syndrome, intestinal lymphoma and ischemic colitis.However, there is less awareness of the differential diagnosis between IBD and the rare intestinal diseases.Based on current literature and personal experience, this editorial introduces various rare intestinal diseases that are easily misdiagnosed as IBD, calling for vigilance in the differential diagnosis of IBD and rare IBD-like diseases.

Cirrhotic portal hypertension(CPH)is a common and critical disease in digestive department.Standardized stratified diagnosis and treatment and chronic disease management of related patients are the most basic requirements in digestive teaching.Based on clinical teaching practice, this paper integrates various teaching methods and concepts, and summarizes the five-step questioning method for clinical teaching of CPH.The clinical teaching effect of this teaching method is remarkable, and the relevant summary is specially performed for the benefit of our colleagues.

OBJECTIVES:Although portal vein thrombosis (PVT) was thought to deteriorate portal hypertension and contribute to poor prognosis, risk stratification remains unclear. This study aimed to evaluate its effect on the risk of variceal rehemorrhage and to develop a competitive risk model in cirrhotic patients with PVT. METHODS:Cirrhotic patients with and without PVT admitted for acute variceal hemorrhage were retrospectively included after matching (1:1) for age, gender and etiology of cirrhosis from two tertiary centers with 1-year follow-up. Those with PVT were subsequently divided into the training and validation cohorts. Cox regression analysis was performed to identify risk factors and develop a competitive risk model, of which the predictive performance and optimal decision threshold were evaluated by C-index, competitive risk curves, calibration curves and decision curve analysis. RESULTS:Among 398 patients, PVT significantly increased the variceal rehemorrhage risk. Multivariate Cox regression analysis identified that the Child-Turcotte-Pugh score (P = 0.013), chronic PVT (P = 0.025), C-reactive protein (P < 0.001), and aspartate aminotransferase (P = 0.039) were independently associated with variceal rehemorrhage, which were incorporated into the competitive risk model, with high C-index (0.804 and 0.742 of the training and validation cohorts, respectively), risk stratification ability, and consistency. The optimal decision range of the threshold probability was 0.2-1.0. CONCLUSION:We confirmed the adverse effect of PVT on variceal rehemorrhage and developed a competitive risk model for variceal rehemorrhage in cirrhotic patients with PVT, which might be conveniently used for clinical decision-making.

AIM:This study aimed to assess the prognostic significance of virtual portal pressure gradient (vPPG) response to carvedilol in patients with compensated cirrhosis (CC).METHODS:Compensated cirrhosis patients with high-risk varices were prospectively enrolled to receive carvedilol for prevention of first variceal hemorrhage (VH) and followed up for 1 year. The vPPG response was defined as a reduction of vPPG >10% from baseline after 1-month therapy. Logistic and Cox regression analyses were performed to identify independent predictors for vPPG response and first decompensation, respectively. Competitive risk models were constructed to predict disease progression, and validated using the C-index, Kaplan-Meier analysis, competitive risk analysis, and calibration curves.RESULTS:A total of 129 patients completed this study, of whom 56 (43.4%) achieved vPPG response and were referred as vPPG responders. Baseline vPPG, red color sign, Model for End-stage Liver Disease score, serum monocyte chemoattractant protein-1 (MCP-1), and laminin levels significantly correlated with vPPG response, which itself was further documented as an independent predictor of VH, ascites, and overall decompensation events in CC. Moreover, the red color sign or Child-Turcotte-Pugh score effectively predicted VH, while ascites correlated well with portal flow velocity or MCP-1. The predictive models for VH and ascites showed a good discrimination with C-index values of 0.747 and 0.689 respectively, and the high consistency on calibration curves.CONCLUSION:The vPPG response could be used as a noninvasive tool for prediction of disease progression in patients with CC.

Fatty pancreas(FP)is not uncommon as a component of obesity-related metabolic syndrome.It is not only closely related to metabolic syndrome-related diseases, but also plays a causative role in the risk of pancreatitis, pancreatic cancer and pancreatic fistula.Compared with metabolic dysfunction-associated fatty liver disease(MAFLD), current status is not optimistic about the degree of attention and awareness of FP that even occurs earlier than MAFLD.This editorial outlines several important issues of FP in pathogenesis, pathophysiology, correlation with other clinical diseases, diagnosis, prevention and treatment status, and summarizes the limitations and controversies of the current understanding in FP, in order to attract attention to its basic and clinical research.

Pharmacological inhibition of cyclooxygenase-2 (COX-2) activity ameliorated the severity of non-alcoholic steatohepatitis (NASH) rats. It is not completely understood that the role of COX-2 inhibitor celecoxib on adiponectin receptors (Adipo-R1/R2) expression in different tissues in NASH rats. Sprague-Dawley male NASH rats induced by a high-fat diet (HFD) were administrated with or without celecoxib for 8 weeks. Biochemical parameters of liver function, glucose, and lipid metabolism, and the levels of adiponectin, tumor necrosis factor-alpha (TNF-α), prostaglandin E2 (PGE2) in the serum or liver were collected according to the standard protocols. The mRNA and protein levels of Adipo-R1, Adipo-R2, and COX-2 in the liver, muscle, and visceral fat were performed by quantitative real-time polymerase chain reaction (q-PCR) and Western blot analysis, respectively. The results showed that celecoxib ameliorated the various clinical indicators and pathological characteristics in the NASH rats, including body weight, liver function, liver index, and redox activities in serum and hepatic samples. The serum concentrations of adiponectin and TNF-α and PGE2 were negatively correlated. As expected, these ameliorative effects of celecoxib were associated with the gene and protein levels up-regulation of Adipo-R1, Adipo-R2 in the liver and visceral fat tissues, and seeming to be compensatory down-regulation expression in muscle tissues (P <0.05). Additionally, COX-2 protein expression was negatively correlated with serum adiponectin levels, protein expression of adiponectin receptors from the liver and visceral fat, conversely, positively correlated with those from the muscle. Our current study demonstrate that celecoxib might effectively alleviate NASH rats in a unique manner closely relevant to redistributing the expression of adiponectin receptors in the liver, visceral fat, and muscle. However, the precise molecular mechanism needs further study.

Background: Endoscopic primary bile reflux is one of the main diagnostic criteria for bile reflux gastritis (BRG). Presently, the risk factors and prediction models of endoscopic primary bile reflux (EPBR) in gastropathy patients who cannot or will not undergo endoscopy due to contraindications are not clear. Thus, this study aimed to evaluate the risk factors of EPBR and to establish and verify a prediction model. Methods: A series of 844 patients (564 subjects with EPBR and 280 control subjects) were retrospectively selected for this study and divided into a training set (n = 591) and a validation set (n = 253) according to the usual ratio of 70:30% for the subsequent internal validation of the logistic regression model for EPBR. Fifteen parameters that might affect the occurrence of EPBR were collected. Subsequently, univariate and stepwise logistic regression analyses were introduced to reveal the risk factors and the multivariate prediction model. An R package was dedicated to the corresponding internal validation of the EPBR model. Results: The univariate analysis showed that gender, age, smoking, Helicobacter pylori (H. pylori) infection status, metabolic syndrome (MS), non-steroidal anti-inflammatory drugs (NSAIDs) use history, and previous medical histories of chronic liver diseases, cholelithiasis, and erosive gastritis were statistically significant between the two groups (P < 0.05). Multivariate regression described that being a male [OR (95%confidence interval (CI)) = 2.29 (1.50–3.50), P < 0.001], age≥45 years old [OR (95% CI) = 4.24 (2.59–6.96), P < 0.001], H. pylori infection status [OR (95% CI) = 2.34 (1.37–4.01), P = 0.002], MS [OR (95% CI) = 3.14 (1.77–5.54), P < 0.001], NSAIDs use history [OR (95% CI) = 1.87 (1.03–3.40), P = 0.04], cholelithiasis history [OR (95% CI) = 3.95 (2.18–7.18), P < 0.001] and erosive gastritis history [OR (95% CI) = 6.77 (3.73–12.29), P < 0.001] were the risk factors for the occurrence of EPBR. Based on the results of these risk factors, an EPBR prediction model with an adequate calibration and excellent discrimination was established [area under the curve (AUC): 0.839, 95% CI = 0.806–0.872]. Conclusions: Being a male, age ≥ 45 years old, H. pylori infection, histories of MS, NSAIDs use, cholelithiasis, and erosive gastritis appear to be the risk factors for EPBR, and our favorable prediction model might be an option for the prediction of EPBR.

随着非酒精性脂肪性肝病(NAFLD)成为全球第一大慢性肝病后,非酒精性脂肪性肝炎相关肝癌(NASH-HCC)患者逐年增加,并渐成为肝癌最普遍病因.与其他病因肝癌明显不同,NASH-HCC与遗传因素、代谢综合征、肠道菌群改变和持续炎症等危险因素有关,临床上NASH-HCC多发生于年龄较大、男性、肥胖患者,并可由无肝硬化的NAFLD发展而来,在超声、CT及MRI检查中各有其相对特征性的表现.本文就NASH-HCC特征及诊治进展进行综述.

Since December 2019, an outbreak of novel coronavirus pneumonia in Wuhan has swept the country and is listed as a public health emergency of international concern. According to the previous research results of other coronaviruses and the characteristics of digestive clinical work activities, the key personal protection points during the epidemic of the novel coronavirus pneumonia were summarized for reference in the clinical first-line digestive staff. Key words: Novel coronavirus pneumonia; Epidemics; Digestive department; Personal protection

With the 70th anniversary of the founding of the People′s Republic of China, New China′s health business in gastroenterology and hepatology has undergone earth-shaking changes.The department of gastroenterology and hepatology itself is growing dramatically.The spectrum of digestive diseases and the concept of diagnosis and treatment are updating with each passing day.The digestive endoscopy equipment and technology are developing rapidly.Digestive scholars in China are participating in international exchanges actively.Through the review and study of the above contents, much tribute to the achievements of New China′s predecessors for the digestive system disease. Key words: Gastroenterology; Health business; New China

目的 比较脂肪肝(fatty liver,FL)和脂肪胰(fatty pancreas,FP)患者营养状态的差异,为重视和规范脂肪胰的营养干预提供依据.方法 2017年1月-2018年8月前瞻性地入选脂肪肝和/或脂肪胰患者、健康体检者共372例.分为脂肪肝组(112例)、脂肪胰组(102例)、脂肪肝合并脂肪胰组(80例)和健康体检对照者(78例).检测不同组别患者BMI、三角肌皮褶厚度(triceps skin fold,TSF)、上臂中点围(mild arm circumference,MAC)、上臂肌围(arm muscle circumference,AMC)和手握力等人体测量指标,多频电阻抗分析法检测人体成分指标、全自动生化仪检测实验室营养指标.结果 和FL组相比,FP组BMI[(27.36±7.87) vs (24.34±8.62) kg/m2,P=0.02]、人体脂肪组织量[(24.56±7.01) vs (18.96±8.44) kg,P=0.00)]、三酰甘油[(2.81±0.49) vs (1.72±0.48) mmol/L,P=0.04)、空腹血糖[(6.22±0.87) vs (5.54±0.98) mmol/L,P=0.00]和胰岛素抵抗指数(6.21±2.08 vs 3.91±0.84,P=0.00)紊乱更为明显,差异均有统计学意义(P＜0.05).合并组和FL相比有类似的结果,同时合并组三酰甘油较FP组明显升高[(2.81±0.49) vs(3.57±0.54) mmol/L,P=0.01)].结论 脂肪胰较脂肪肝患者更易发生胰岛素抵抗和营养过剩问题,亟需重视和积极营养干预脂肪胰.

In recent years, the number of patients with inflammatory bowel disease in China has increased dramatically, but it is currently underappreciated or underestimated in the clinical practice.It is urgent to carry out standardized diagnosis and treatment.In order to attract the attention of digestive specialists, according to personal clinical experience and literature reports, several hot issues in the diagnosis, differential diagnosis and standardized individualized treatment that should be taken extra care in the diagnosis and treatment of inflammatory bowel disease have been analyzed. Key words: Inflammatory bowel disease; Ulcerative colitis; Crohn disease

为了规范化地培养临床医学硕士生,2010年以后国家正式将临床医学硕士生分为专业学位型和科学学术学位型.前者与住院医师规范化培训制度相结合,偏重于临床医疗,后者偏重于基础科研.但在临床教学中发现二者皆有短板.本文结合硕士生今后个人发展需要,提出几点建议.

Objective To investigate the changes in the diagnostic and therapeutic methods for Lemmel′s syndrome over the past 20 years in China,and to provide experience for standardized diagnosis and treatment of this disease. Methods A retrospective analysis was performed for the clinical data of 23 patients with Lemmel′s syndrome who were diagnosed and treated in Tongji Hospital of Tongji University from Janu-ary 1998 to June 2017 and 384 patients with Lemmel′s syndrome reported in China during the same period of time(407 patients in total). According to the admission time,the patients were divided into groups A(139 patients admitted from 1998 to 2007)and B(268 patients admitted from 2008 to 2017). The patients′clinical features,diagnostic and therapeutic methods,and prognosis were recorded. The t-test was used for comparison of normally distributed continuous data between groups,and the Wilcoxon rank sum test was used for comparison of non-normally distributed continuous data between groups;the chi-square test was used for comparison of categorical data between groups. Results Compared with group A,group B had significantly higher age of onset(67.8 ± 17.8 vs 62.3 ± 12.3,t= -13.238,P= 0.019) and incidence rate of cholangitis(45.9% vs 32.4%,χ2=6.903,P=0.009). As for diagnostic methods,compared with group A,group B had a significantly higher proportion of patients who used multi-slice spiral CT(MSCT)(26.9% vs 8.6%,χ2=18.576,P<0.001), endoscopic ultrasonography(EUS)(15.7% vs 5.8%,χ2=8.352,P=0.004),magnetic resonance cholangiopancreatography(MRCP) (75.0% vs 33.1%,χ2=67.303,P<0.001),or endoscopic retrograde cholangiopancreatography(ERCP)(63.4% vs 36.7%,χ2=26.377,P<0.001),while the two groups had a similar false positive rate(22.8% vs 28.1%,χ2=1.385,P=0.239). As for therapeu-tic methods,compared with group A,group B had a significantly higher proportion of patients who underwent ERCP combined with conserva-tive pharmacotherapy and surgical operation(χ2=34.758,P<0.001). There was a significant difference in recurrence rate between endo-scopic surgery group and conservative pharmacotherapy group(χ2=40.211,P<0.001),as well as between surgical operation group and conservative pharmacotherapy group(χ2=26.785,P<0.001);there was no significant difference in recurrence rate between surgical oper-ation group and endoscopic surgery group(χ2=0.055,P=0.815),but endoscopic surgery had the advantages of minimal invasiveness, fast recovery,and low costs. Conclusion Age of onset of Lemmel′s syndrome is gradually increasing. MSCT,EUS,MRCP,and ERCP ap-plied alone or in combination are major diagnostic methods,and ERCP is the preferred therapeutic method for Lemmel′s syndrome.

1934 年 ,Lemmel[1] 报道了十二指肠乳头旁憩室(juxtapapillary duodenal diverticulum ,JDD)压迫胆胰管致胆管炎、梗阻性黄疸或胰腺炎 ,而不伴胆总管结石的疾病特征 ,称Lemmel综合征.根据解剖和病理生理特点 ,Lemmel综合征又被称为十二指肠憩室梗阻性黄疸综合征、十二指肠乳头旁憩室-胆胰管综合征、壶腹旁憩室综合征、乳头旁憩室综合征等 ,其以间歇性黄疸、发热、上腹痛为主要临床表现 ,是梗阻性黄疸少见的病因之一(约占0 .8％ )[2 ] .随着多层螺旋计算机断层成像(multi-slice spiral computed tomograpy , MSCT )、磁 共 振 胆 胰 管 成 像 ( magnetic resonance cholangiopancreatography ,MRCP)和内镜逆行性胆胰管造影(endoscopic retrograde cholangiopancreatography ,ERCP)技术的迅猛发展 ,既往被认为罕见的 Lemmel综合征病例报道逐年增多.但目前临床仍对其认识或重视不足 ,如何个体化、规范地选择诊疗方案尚待探讨 . 现将近年国内外Lemmel综合征的临床特征和诊治情况归纳总结如下 ,以期引起临床医师对此疾病的重视.