Cellular and Molecular Gastroenterology and Hepatology最新文献

{"title":"HIF-2α-Driven Lipogenesis and Inflammation in MASLD: Role of ATF4 Signaling.","authors":"Zhe Yang, Niujian Wu, Xin Li, Yun Li, Zhanjin Lu, Taoping Sun, Zhixing Cao, Xianghong Wang, Chen Yang, Shisong Han, Hongyun Lu","doi":"10.1016/j.jcmgh.2025.101651","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101651","url":null,"abstract":"<p><strong>Background & aims: </strong>Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by an imbalance of lipid metabolism and chronic inflammation. Emerging evidence suggests a role for Hypoxia-inducible Factor 2α (HIF-2α) in MASLD progression. However, the mechanistic linkage between HIF-2α and steatohepatitis progression remains largely elusive.</p><p><strong>Methods: </strong>Here, hepatocyte-specific HIF-2α knockout mice were used to investigate the pathophysiological role of HIF-2α in MASLD. Multiple gain- and loss-of-function experiments in primary hepatocytes and established human hepatocyte cell lines were performed to elucidate the molecular mechanisms by which HIF-2α contributes to MASLD progression.</p><p><strong>Results: </strong>Compared to their wild-type littermates, hepatocyte-specific HIF-2α knockout mice exhibited a substantial reduction in HFD-induced hepatic steatosis and inflammatory signaling. Furthermore, HIF-2ɑ deficiency in primary hepatocytes and both L02 and MIHA cell lines markedly inhibited the lipid accumulation, inflammation, and endoplasmic reticulum stress in vitro upon FFAs challenge. Mechanistically, HIF-2 directly bound to the promoter region of protein kinase RNA-like ER kinase (PERK), leading to the activation of the activating transcription Factor 4 (ATF4) signaling under metabolic stress, thereby aggravating lipogenesis while inhibiting lipid oxidation in hepatocytes.</p><p><strong>Conclusion: </strong>These data indicate that HIF-2α acts as a contributing factor to MASLD progression via ATF4 signaling.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101651"},"PeriodicalIF":7.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How first foods promote intestinal epithelial maturation: Lessons learnt from suckling rabbits.","authors":"Vanesa Muncan","doi":"10.1016/j.jcmgh.2025.101649","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101649","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101649"},"PeriodicalIF":7.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Etomidate improves antitumor immunity by suppressing PD-L1 expression in hepatocellular carcinoma cells.","authors":"Jiali Xu, Qing Ji, Yining Chen, Yu Xu, Zhihui Wang, Zhenyu Yuan, Dapeng Gao, Lidong Zhang, Cunming Liu, Qing Li, Liren Zhang, Jingjing Dai","doi":"10.1016/j.jcmgh.2025.101652","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101652","url":null,"abstract":"<p><strong>Background & aims: </strong>Etomidate, a prevalent intravenous anesthetic agent, has been implicated in the attenuation of tumorigenesis. Our recent investigations elucidated its capacity to impede the malignant progression of hepatocellular carcinoma (HCC). This study aims to elucidate how etomidate modulates the immunosuppressive tumor microenvironment in HCC.</p><p><strong>Methods: </strong>To investigate the multifaceted effects and underlying molecular mechanisms of etomidate, we employed an integrative approach encompassing in vitro and in vivo systems, including patient-derived HCC organoids, three-dimensional co-culture platforms, patient-derived xenografts, and orthotopic HCC models. A suite of advanced methodologies such as single-cell cytometry by time-of-flight (CyTOF), multiplex immunohistochemistry, and flow cytometric analyses were applied.</p><p><strong>Results: </strong>Our data reveal that etomidate suppresses PD-L1 expression in HCC cells, thereby potentiating antitumor immunity. Mechanistically, etomidate inhibits the JAK2/STAT3 axis in tumor cells, leading to reduced PD-L1 transcription and increased infiltration and activation of cytotoxic CD8⁺ T lymphocytes.</p><p><strong>Conclusions: </strong>These findings support the hypothesis that etomidate enhances antitumor immunity and boosts the therapeutic efficacy of immune checkpoint blockade, thereby laying a theoretical foundation for precision immunotherapy in HCC.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101652"},"PeriodicalIF":7.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anesthetic Agents as Modulators of Anti-Tumor Immunity: Repurposing Etomidate for Hepatocellular Carcinoma Therapy.","authors":"Hanchao Lin, Qiongzhu Dong","doi":"10.1016/j.jcmgh.2025.101650","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101650","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101650"},"PeriodicalIF":7.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CADM1 Emerges as a Biomarker and Therapeutic Opportunity in Inflammatory Bowel Disease.","authors":"Randy S Longman","doi":"10.1016/j.jcmgh.2025.101648","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101648","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101648"},"PeriodicalIF":7.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145187593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting LOXL1-expressing hepatic stellate cell inhibits fibrogenesis and sinusoid angiogenesis via LOXL1/RUNX1/VEGFA axis during progression of liver fibrosis.","authors":"Xuzhen Yan, Qi Han, Yiwen Wang, Weiyu Li, Ning Zhang, Xu Fan, Wei Chen, Hong You, Aiting Yang","doi":"10.1016/j.jcmgh.2025.101637","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101637","url":null,"abstract":"<p><strong>Background & aims: </strong>Hepatic stellate cells (HSCs) are the major source of excessive production of extracellular matrix (ECM) proteins and act as a hub for intrahepatic fibrosis signaling. While extensive crosstalk between HSCs and liver sinusoidal endothelial cells (LSECs) significantly influences disease progression, the detailed mechanisms remain poorly understood. Here, we investigated the role of LOXL1, a pivotal enzyme in ECM cross-linking, in crosstalk between HSCs and LSECs during liver fibrosis.</p><p><strong>Methods: </strong>Coculture systems (EA.hy926/LX2 or LSECs/HSCs) were used to investigate signaling crosstalk. HSC-specific Loxl1 knockout mice were generated and experimental liver fibrosis was induced using a high-fat choline-deficient amino acid-defined (HFCDAA) diet or chronic carbon tetrachloride (CCl₄) exposure. Liver samples were assessed by histology, scanning electron microscopy, immunostaining, and qPCR. Liver tissue and HSCs were analyzed by RNA sequencing to study LOXL1's mechanisms regulating liver fibrosis.</p><p><strong>Results: </strong>LOXL1 in HSCs modulated ECM composition changes in endothelial cells in coculture studies. LOXL1 loss in HSCs suppressed HSC activation, LSEC capillarization, and macrophage infiltration, improved ECM remodeling, and attenuated liver fibrosis in HFCDAA-fed and CCl₄-exposed mice. Our RNA sequencing data, corroborated by public database analyses, indicated RUNX1 was implicated in HSC activation and LOXL1-mediated angiogenesis. We propose that LOXL1 enhances HSC activation and LSEC capillarization through the RUNX1/VEGFA signaling axis CONCLUSIONS: Our study reveals novel mechanistic insights into liver fibrosis, highlighting HSC-derived LOXL1 as a central modulator of disease initiation and progression. Targeting the LOXL1/RUNX1/VEGFA axis offers a promising therapeutic strategy for liver fibrosis.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101637"},"PeriodicalIF":7.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145180044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"R-Spondin1 regulates fate of enteric neural progenitors via differential LGR4/5/6-expression in mice and humans.","authors":"Melanie Scharr, Simon Scherer, Jörg Fuchs, Bernhard Hirt, Peter H Neckel","doi":"10.1016/j.jcmgh.2025.101642","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101642","url":null,"abstract":"<p><strong>Background & aims: </strong>Regeneration and cytodifferentiation of various adult epithelial stem cell compartments are controlled by the WNT-agonist R-Spondin1 (RSPO1) and the Leucin-rich-repeat-containing G-protein-coupled-receptors (LGR4/5/6). We hypothesized that RSPO1-LGR-signaling is also involved in regulating neuroregeneration and homeostasis of the postnatal enteric nervous system (ENS).</p><p><strong>Methods: </strong>We isolated neural crest-derived ENS-cells from wnt1-tomato mice and patient samples, which were evaluated using pharmacological in vitro studies under RSPO1 stimulation. We use proliferation assays (BrdU-incorporation, Ki67-staining), as well as neuronal differentiation screenings. We performed FACS-based in vitro assays to stratify human ENS-cells for LGR-receptor expression, and to characterize them by immunofluorescence co-labeling studies in vivo.</p><p><strong>Results: </strong>If applied to murine and human ENS-progenitors, RSPO1 led to an increased proliferation (P=.002), followed by enhanced enteric neurogenesis (P<.001). This coincided with an upregulation of LGR4 expression during ENS-progenitor proliferation (P≤.001) in vitro. In contrast, we observed a reduced proliferation in ENS-progenitors expressing LGR5 (P≤.001), while LGR6 was not expressed by proliferative ENS-progenitors (P≤.05). Instead, LGR5 and LGR6 expression increased over the course of induced neuronal differentiation (LGR5: P≤.001 and LGR6: P≤.05), consistent with the in vivo expression.</p><p><strong>Conclusions: </strong>LGR-receptor expression therefore might represent a previously unknown mechanism influencing the fate decision of ENS-progenitor cells between proliferation and neuronal differentiation. Thus, our study is essential for our understanding of regenerative aspects of the postnatal ENS in health and disease.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101642"},"PeriodicalIF":7.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145152129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prostanoids in Liver Repair and Regeneration: Biosynthesis, Receptors, and Intercellular Communication.","authors":"Xinzhi Li, Xiaobing Xu, Wenjie Lai, Ai Jiang, Na Zhou, Ying Yu","doi":"10.1016/j.jcmgh.2025.101645","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101645","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101645"},"PeriodicalIF":7.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145152099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Myeloid Lineage Signifying Anti-Tumor Necrosis Factor Resistance in Crohn's Disease.","authors":"Sachith Munasinghe, Duke Geem, Kodhai Duraiarasan, Sushma C Maddipatla, Shanta Murthy, Yeonjoo Hwang, Ranjit S Pelia, Murugadas Anbazhagan, Garima Sharma, Vikram Koti, Irina Geiculescu, Barbara J Niklinsa-Schirtz, Cary Sauer, Raghavan Chinnadurai, Vasantha L Kolachala, Jason D Matthews, Subra Kugathasan","doi":"10.1016/j.jcmgh.2025.101636","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101636","url":null,"abstract":"<p><strong>Background: </strong>While anti-TNF therapy has improved Crohn's disease (CD) management, the development of a refractory phenotype having resistance to the drug is not uncommon. The mechanisms behind this anti-TNF non-response are unknown but are likely multifactorial. Here, we examined myeloid cells expressing signal regulatory protein α (SIRPα) for their potential role in refractory CD.</p><p><strong>Methods: </strong>Response to anti-TNF was defined as having reached endoscopic and histological healing, while non-responders did not. Isolated cells from peripheral blood and mucosal biopsies were analyzed by high dimensional flow cytometry, single-cell and bulk RNA sequencing, and Luminex. Ileal organoids were also challenged with secretomes from stimulated SIRPα⁺ cells.</p><p><strong>Results: </strong>Amongst the CD phenotypes, anti-TNF refractory CD patients had the highest levels of CD33⁺HLA-DR⁺CD11c⁺SIRPα⁺ cells in their intestinal mucosa, but the levels in peripheral blood were unchanged. SIRPα⁺ cells from the gut displayed a higher pro-inflammatory transcriptome, with increased levels of IL-6, TNFα, p40, and IL-1β expression. When isolated and stimulated in vitro with flagellin, these SIRPα⁺ cells showed a more pro-inflammatory transcriptome during CD47 ligation than with an IgG control. Moreover, the secretomes of flagellin/CD47-stimulated SIRPα⁺ cells from refractory CD patients increased cell death and promoted gene expression associated with Rho GTPase and innate immune responses in epithelial cells, while downregulating their gene expression involved in RNA, lipid metabolism, and adaptive response signaling.</p><p><strong>Conclusion: </strong>Increased levels of myeloid lineage expressing CD33⁺HLA-DR⁺CD11c⁺SIRPα⁺ cells in the intestinal mucosa negatively impact epithelial cell function, possibly explaining one mechanism for anti-TNF resistance. The abundance of mucosal SIRPα⁺cells should be further explored as a biomarker and therapeutic target.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101636"},"PeriodicalIF":7.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145152057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diverse Misfolding Mutant Digestive Enzymes Cause Chronic Pancreatitis through Common Pathways.","authors":"Steven J Wilhelm, Grace E Curry, Neel Matiwala, Jianguo Lin, Tran Quach, Mark E Lowe, Miklós Sahin-Tóth, Xunjun K Xiao","doi":"10.1016/j.jcmgh.2025.101638","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101638","url":null,"abstract":"<p><strong>Background and aims: </strong>Increasing evidence suggests that protein misfolding and proteotoxicity is an important mechanism of chronic pancreatitis (CP) in patients with genetic variants. Two mouse models carrying misfolding digestive enzyme variants, CPA1 N256K and PNLIP T221M, recapitulate the human CP phenotype. We hypothesized that both models develop CP through similar disease mechanisms.</p><p><strong>Methods: </strong>We conducted a comprehensive analysis of mice aged 1 to 6 months using histology, immunohistochemistry, protein immunoblotting, qPCR, transmission electron microscopy (TEM), and RNA-Seq analysis to characterize pancreatic pathological changes.</p><p><strong>Results: </strong>Both homozygous models exhibited CP hallmarks, including progressive acinar cell loss, inflammation, fibrosis, and fatty replacement. CP progression was slower and less severe in Cpa1 N256K mice compared to Pnlip T221M mice, and heterozygous mice showed slower CP development than homozygotes. Both mutant proteins misfolded in the pancreas, inducing ER stress and activating the unfolded protein response. RNA-Seq analysis revealed slight differences in altered pathways at 1 month, but these differences disappeared by 3 months. Notably, apoptosis pathways were among the top up-regulated pathways, confirmed by qPCR and immunohistochemistry. Differential expression and pathway analyses indicated early activation of both intrinsic and extrinsic apoptosis pathways elicited through multiple mechanisms.</p><p><strong>Conclusions: </strong>Our study demonstrates that Cpa1 N256K and Pnlip T221M mice develop CP through similar mechanisms with slight differences in progression and severity. Both models could serve as invaluable tools for developing and testing CP therapies. Targeting cell death pathways for therapy may be unfeasible given their redundancy. Instead, effective therapeutic strategies should focus on reducing the burden of misfolded digestive enzymes in the pancreas.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101638"},"PeriodicalIF":7.1,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145139453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}