Cellular and Molecular Gastroenterology and Hepatology最新文献

{"title":"Suppression of Hepatocellular Carcinoma by Deletion of SIRT2 in Hepatocytes via Elevated C/EBPβ/GADD45γ.","authors":"Fang Wang, Claudia Rose Keating, Yingchen Xu, Wei Hou, Greg Malnassy, Kyle Boedeker, Aldeb Perera, Eugene Ham, Diya Patel, Xianzhong Ding, Wei Qiu","doi":"10.1016/j.jcmgh.2025.101494","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101494","url":null,"abstract":"<p><strong>Background & aims: </strong>There is a gap in our understanding of mechanisms promoting hepatocellular carcinoma (HCC), and this limits our ability to provide targeted therapy interventions for HCC. In HCC samples, NAD-dependent deacetylase sirtuin 2 (SIRT2) levels are increased and associated with a significantly worse prognosis, but the role of SIRT2 in hepatocarcinogenesis remains controversial.</p><p><strong>Methods: </strong>To assess the role of SIRT2 in hepatocarcinogenesis, we used a hepatocyte-specific knockout of SIRT2 and two plasmid overexpression HCC models: MET/CAT and AKT/Nras. RNA-sequencing of mouse liver tissue was performed, and mechanistic findings were confirmed using IHC, qPCR, western blot, and CCK-8.</p><p><strong>Results: </strong>Using the MET/CAT and AKT/Nras models, we found that SIRT2 is a significant mediator of liver tumorigenesis, with the knockout of SIRT2 delaying tumor growth. RNA-sequencing of MET/CAT-driven tumor tissue showed an increase in GADD45γ in SIRT2 knockout mice compared to WT. GADD45γ, or growth arrest and DNA-damage-inducible protein gamma, is a known tumor suppressor, but the regulation of GADD45γ by SIRT2 has not been shown. C/EBP proteins are known to regulate GADD45γ expression, and we found that C/EBPβ expression was increased in SIRT2 knockout livers and HCC cells. Also, C/EBPβ knockdown reversed GADD45γ expression and growth suppression following SIRT2 inhibition. Finally, C/EBPβ or GADD45γ overexpression significantly suppressed MET/CAT-induced HCC development.</p><p><strong>Conclusions: </strong>SIRT2 is a potent tumor promotor in HCC that negatively regulates GADD45γ expression through C/EBPβ. The SIRT2-C/EBPβ-GADD45γ pathway elucidates a novel mechanism in HCC and establishes SIRT2 as a therapeutic target for HCC patients.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101494"},"PeriodicalIF":7.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625849","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":"Piezo1 specific deletion in macrophage protects the progression of chronic inflammatory bowel disease in mice.","authors":"Yuman Wang, Tianjiao Chu, Chengzhen Meng, Yifei Bian, Jing Li","doi":"10.1016/j.jcmgh.2025.101495","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101495","url":null,"abstract":"<p><strong>Background &aims: </strong>Piezo1, a recently identified mechanically-activated nonselective cation channel protein, demonstrates sensitivity to various mechanical stimuli, such as matrix stiffness and shear stress. While accumulating evidence implicates Piezo1 channels in numerous physiological and pathophysiological processes, its involvement in dextran sulfate sodium (DSS)-induced acute and chronic inflammatory bowel disease (IBD) remains incompletely understood. This study aimed to investigate the effect of Piezo1 channels in macrophage polarization and its associated functions in IBD.</p><p><strong>Methods: </strong>DSS-induced inflammatory bowel disease model was established in Piezo1^td/Tdt or Piezo1^fl/fl and Piezo1^△LysM male mice. Additionally, bone marrow-derived macrophages (BMDMs) from Piezo1^fl/fl and Piezo1^△LysM male mice were isolated to elucidate the downstream targets of Piezo1 and the associated underlying molecular mechanisms.</p><p><strong>Results: </strong>Our findings revealed that Piezo1 deficiency in macrophages could protect mice from DSS-induced chronic IBD, as evidenced by improved colon length and the preservation of colon structure. The mitigation of inflammation during chronic IBD progression was observed with Piezo1 deficiency in macrophages, characterized by reduced macrophage accumulation, M1 macrophage polarization, T helper 1 (T_H1) infiltration, and decreased inflammatory cytokine secretion. Further investigations unveiled that Piezo1-deficient macrophages inhibit the expression and activity of NLRP3 and NF-κB in colon tissues and BMDMs while regulating the nuclear translocation of p65. Conversely, macrophage Piezo1 activation enhanced inflammatory cytokine secretion by activating NLRP3/NF-κB pathways.</p><p><strong>Conclusions: </strong>Myeloid Piezo1 mediates colonic immune response, and disrupting Piezo1 inhibits the progression of chronic inflammatory bowel disease. This study provides hitherto undocumented evidence of the pivotal role of macrophage Piezo1 channels in regulating the progression of chronic inflammatory bowel disease. Targeting macrophage Piezo1 may offer a promising therapeutic strategy against chronic inflammatory bowel disease.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101495"},"PeriodicalIF":7.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627223","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":"Inhibition of Ribosome Biogenesis in vivo Causes p53-Dependent Death and p53-Independent Dysfunction.","authors":"Charles J Cho, Thanh Nguyen, Amala K Rougeau, Yang-Zhe Huang, Sarah To, Xiaobo Lin, Supuni Thalalla Gamage, Jordan L Meier, Jason C Mills","doi":"10.1016/j.jcmgh.2025.101496","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101496","url":null,"abstract":"<p><strong>Background & aims: </strong>While it is well-known that ribosomes are critical for cell function, and their synthesis (known as ribosome biogenesis; \"RiBi\") is energy-intensive, surprisingly little is known about RiBi in vivo in adult tissue.</p><p><strong>Methods: </strong>Using a mouse model with conditional deletion of Nat10, an essential gene for RiBi and subsequent translation of mRNA, we investigated the effects of RiBi blockade in vivo, with a focus on pancreatic acinar cells during homeostasis and tumorigenesis.</p><p><strong>Results: </strong>We observed an unexpected latency of several weeks between Nat10 deletion and onset of structural and functional abnormalities and p53-dependent acinar cell death. While deletion of Trp53 rescued acinar cells from apoptotic cell death, Nat10^Δ/Δ; Trp53^Δ/Δ acinar cells remained morphologically and functionally abnormal. Deletion of Nat10 in acinar cells blocked Kras-oncogene-driven pancreatic ductal adenocarcinoma, regardless of Trp53 mutation status.</p><p><strong>Conclusion: </strong>Together, our results provide initial insights into how differentiated cells respond to defects in RiBi and translation in vivo in various physiological contexts.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101496"},"PeriodicalIF":7.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627206","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":"Attenuating ABHD17 isoforms augments the S-acylation and function of NOD2 and a subset of Crohn's disease-associated NOD2 variants.","authors":"Charneal L Dixon, Noah R Martin, Micah J Niphakis, Benjamin F Cravatt, Gregory D Fairn","doi":"10.1016/j.jcmgh.2025.101491","DOIUrl":"10.1016/j.jcmgh.2025.101491","url":null,"abstract":"<p><strong>Background and aims: </strong>NOD2 is an intracellular innate immune receptor that detects bacterial peptidoglycan fragments. Although nominally soluble, some NOD2 is associated with the plasma membrane and endosomal compartments for microbial surveillance. This membrane targeting is achieved through post-translational S-acylation of NOD2 by the protein acyltransferase ZDHHC5. Membrane attachment is necessary to initiate a signaling cascade in response to cytosolic peptidoglycan fragments. Ultimately, this signaling results in the production of antimicrobial peptides and proinflammatory cytokines. In most cases, S-acylation is a reversible post-translational modification with removal of the fatty acyl chain catalyzed by one of several acyl protein thioesterases. Deacylation of NOD2 by such an enzyme will displace it from the plasma membrane and endosomes, thus preventing signaling.</p><p><strong>Methods: </strong>To identify the enzymes responsible for NOD2 deacylation, we used engineered cell lines with RNA interference and small-molecule inhibitors. These approaches were combined with confocal microscopy, acyl-resin-assisted capture, immunoblotting, and cytokine multiplex assays.</p><p><strong>Results: </strong>We identified α/β-hydrolase domain-containing protein 17 isoforms (ABHD17A, ABHD17B, and ABHD17C) as the acyl protein thioesterases responsible for NOD2 deacylation. Inhibiting ABHD17 increased the plasma membrane localization of wild-type NOD2 and a subset of poorly acylated Crohn's disease-associated variants. This enhanced NOD2 activity, increasing NF-κB activation and pro-inflammatory cytokine production in epithelial cells.</p><p><strong>Conclusions: </strong>These findings demonstrate that ABHD17 isoforms are negative regulators of NOD2. The results also suggest that targeting ABHD17 isoforms could restore functionality to specific Crohn's disease-associated NOD2 variants, offering a potential therapeutic strategy.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101491"},"PeriodicalIF":7.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588322","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":"Cortactin facilitates malignant transformation of dysplastic cells in gastric cancer development.","authors":"Alexis A Guenther, Suyeon Ahn, Jimin Min, Changqing Zhang, Hyuk-Joon Lee, Han-Kwang Yang, Bong Hwan Sung, Alissa M Weaver, Eunyoung Choi","doi":"10.1016/j.jcmgh.2025.101490","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101490","url":null,"abstract":"<p><strong>Background & aims: </strong>Epithelial cancer onset occurs through sequential stages of cell lineage conversion and functional dysregulation. Dysplasia is a precancerous lesion defined as a direct precursor to cancer and is histologically defined as a transition stage between pre-cancer and cancer, but molecular and biological mechanisms controlling its transformation to malignancy are underdetermined. Here, we discover the crucial role of the actin stabilization and exosome secretion-regulatory protein cortactin in dysplastic cell transformation to adenocarcinoma.</p><p><strong>Methods: </strong>We engineered a CRISPR/Cas9-based cortactin knock-out (KO) dysplasia organoid model established from dysplastic tissue and examined malignant roles of cortactin during gastric cancer development in vitro and in vivo.</p><p><strong>Results: </strong>While dysplastic cell identity remained unchanged, the cortactin KO organoids exhibited a decrease in cellular organization and multicellular protrusions, which are considered aggressive features when observed in vitro. When injected into the flank of nude mice, cortactin KO cells failed malignant transformation into adenocarcinoma and solid tumor formation with reduced recruitment of fibroblasts and macrophages. In addition, cortactin KO cells showed diminished exosome secretion levels and adenocarcinoma development was impaired when exosome secretion was inhibited in cortactin WT dysplastic cells.</p><p><strong>Conclusions: </strong>These data suggest that cortactin is a functional element of membrane dynamics, malignant changes, and exosome secretion in dysplastic cells, and solid gastric tumor formation associated with alteration of the tumor microenvironment.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101490"},"PeriodicalIF":7.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586910","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":"Irritable Bowel Syndrome with Diarrhea in Pediatric Patients is Associated with Type 2 and Type 9 T Cells in the Intestinal Mucosa.","authors":"Xin Chen, Brener Carvalho, Anika Sinha, Nanci Pittman, Keith Benkov, Joanne Lai, Maria Curotto de Lafaille, David Dunkin","doi":"10.1016/j.jcmgh.2025.101488","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101488","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101488"},"PeriodicalIF":7.1,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538138","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":"Activation of AMPK by metformin inhibits dedifferentiation of PDGF-BB-induced vascular smooth muscle cells to improve arterial remodeling in cirrhotic portal hypertension.","authors":"Guangbo Wu, Qiang Fan, Min Chen, Guqing Luo, Zhenghao Wu, Jinbo Zhao, Jiayun Lin, Chihao Zhang, Hongjie Li, Xiaoliang Qi, Haizhong Huo, Lei Zheng, Meng Luo","doi":"10.1016/j.jcmgh.2025.101487","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101487","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background & aims: &lt;/strong&gt;Portal hypertension (PHT) is the potentially deadly complication of liver cirrhosis. Intrahepatic vascular resistance and the splanchnic hyperdynamic circulation are two principal driving factors contributing to the maintenance and exacerbation of PHT. However, in the advanced stages of cirrhosis, the fibrotic process in the liver becomes irreversible, leading to persistent and intractable increases in intrahepatic vascular resistance. Arterial remodeling emerges as a crucial mechanism driving the hyperdynamic splanchnic circulation. Therefore, ameliorating the hyperdynamic splanchnic circulation has become an indispensable component of PHT therapeutic strategies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Liver cirrhosis with PHT was induced in the rats by common bile duct ligation (BDL). Based on the transcriptomic sequencing of the mesenteric arteries, we investigated the effects and mechanisms of metformin on the arterial remodeling at different stages of cirrhosis. We further validated potential molecular mechanisms through in vitro experiments using the A7r5 smooth muscle cell line and primary vascular smooth muscle cells (VSMCs).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Our findings revealed the beneficial effects of metformin on liver cirrhosis and PHT in rats following bile duct ligation (BDL) for 4 and 6 weeks. Metformin was observed to ameliorate PHT and splanchnic hyperdynamic circulation in BDL rats, even in the advanced stages of liver cirrhosis. This effect was evidenced by reduced portal pressure (PP) and cardiac output (CO), decreased SMA flow, accompanied by improvements in systemic vascular resistance (SVR) and SMA resistance. Moreover, chronic inflammation in BDL rats was alleviated by metformin, which might inhibit the driving factors of angiogenesis and arterial remodeling. Notably, SMA dilation and arterial remodeling in BDL rats were potent alleviated following metformin treatment. Metformin ameliorated arterial remodeling in BDL rats by inhibiting the dedifferentiation of contractile VSMCs, resulting in the upregulation of contractile protein expressions such as α-SMA and SM22α. PDGF-BB/PDGFR-β signaling exerted crucial roles in regulating the VSMCs cell phenotype. Activation of AMPK by metformin blocked the downstream pathway of PDGF-BB/PDGFRβ. Furthermore, in vitro cell experiments, VSMCs were respectively treated with AMPK activator metformin or AMPK inhibitor Compound C. We revealed the molecular mechanism that metformin inhibited the phenotypic switching of A7r5 cells induced by PDGF-BB and primary VSMCs from BDL rats, which was mediated by activating AMPK to enhance the expression of contractile protein α-SMA. These findings suggest that AMPK can ameliorate the progression of arterial remodeling during PHT via suppressing the PDGF-BB/PDGFRβ signaling pathway, thereby offering novel insights into seek PHT treatment approaches.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Our findings revealed that metformin","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101487"},"PeriodicalIF":7.1,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538136","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":"Studies of Slc30a10 deficiency in mice reveal that intestinal iron transporters Dmt1 and ferroportin transport manganese.","authors":"Milankumar Prajapati, Jared Z Zhang, Grace S Chong, Lauren Chiu, Courtney J Mercadante, Heather L Kowalski, Olga Antipova, Barry Lai, Martina Ralle, Brian P Jackson, Tracy Punshon, Shuling Guo, Mariam Aghajan, Thomas B Bartnikas","doi":"10.1016/j.jcmgh.2025.101489","DOIUrl":"10.1016/j.jcmgh.2025.101489","url":null,"abstract":"<p><strong>Background and aims: </strong>SLC11A2 (DMT1) and SLC40A1 (ferroportin) are essential for dietary iron absorption, but their role in manganese transport is debated. SLC30A10 deficiency causes severe manganese excess due to loss of gastrointestinal manganese excretion. Patients are treated with chelators but also respond to oral iron, suggesting that iron can outcompete manganese for absorption in this disease. Here we determine if Dmt1 and ferroportin can transport manganese using Slc30a10-deficient mice as a model.</p><p><strong>Methods: </strong>Manganese absorption and levels and other disease parameters were assessed in Slc30a10^-/- mice with and without intestinal Dmt1 and ferroportin deficiency using gastric gavage, surgical bile collections, multiple metal assays, and other techniques. The contribution of intestinal Slc30a10 deficiency to ferroportin-dependent manganese absorption was explored by determining if intestinal Slc30a10 deficiency increases manganese absorption in a mouse model of hereditary hemochromatosis, a disease of iron excess due to ferroportin upregulation.</p><p><strong>Results: </strong>Manganese absorption was increased in Slc30a10-deficient mice despite manganese excess. Intestinal Dmt1 and ferroportin deficiency attenuated manganese absorption and excess in Slc30a10-deficient mice. Intestinal Slc30a10 deficiency increased manganese absorption and levels in the hemochromatosis mouse model.</p><p><strong>Conclusions: </strong>Aberrant absorption contributes prominently to SLC30A10 deficiency, a disease previously attributed to impaired excretion, and is dependent upon intestinal Dmt1 and ferroportin and exacerbated by loss of intestinal Slc30a10. This work expands our understanding of overlaps between manganese and iron transport and the mechanisms by which the body regulates absorption of two nutrients that can share transport pathways. We propose that a reconsideration of the role of Dmt1 and ferroportin in manganese homeostasis is warranted.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101489"},"PeriodicalIF":7.1,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538200","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":"Fibroblast Growth Factor 20 Attenuates Colitis by Restoring Impaired Intestinal Epithelial Barrier Integrity and Modulating Macrophage Polarization via S100A9 in an NF-κB Dependent Manner.","authors":"Dong Zhen, Songxue Wang, Zhen Liu, Yiyuan Xi, Hanlin Du, Ningrui Wang, Xiaotang Gao, Zhuofeng Lin, Fan Wu","doi":"10.1016/j.jcmgh.2025.101486","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101486","url":null,"abstract":"<p><strong>Background & aims: </strong>Exogenous recombinant Fibroblast growth factor 20 (FGF20) protein has been proved that can treat ulcerative colitis, however, its mechanism of action remains unclear. This study aimed to explore the role and mechanism of action of FGF20 in ulcerative colitis.</p><p><strong>Methods: </strong>Data from patients with ulcerative colitis were analyzed using the Gene Expression Omnibus dataset. A murine colitis model was established by administering 2% dextran sodium sulfate (DSS). FGF20 knockout (KO) mice and Adeno-associated viruses (AAV)-FGF20 treated-mice were used to elucidate the specific mechanisms. Proteomic analysis was conducted to identify differentially expressed genes.</p><p><strong>Results: </strong>FGF20 levels were significantly elevated in the colonic tissues of both subjects and mice with colitis. FGF20 deficiency exacerbated DSS-induced colitis; in contrast, FGF20 replenishment alleviated colitis through two principal mechanisms-restoration of impaired intestinal epithelial barrier integrity and inhibition of M1 macrophage polarization. Notably, S100A9 was identified as a pivotal downstream target of FGF20, which was further demonstrated by pharmacological inhibition and overexpression experiments of S100A9 using paquinimod (a specific inhibitor of S100A9) and AAV-S100A9 in FGF20 KO and AAV-FGF20 mice with colitis, respectively. Additionally, the NF-κB pathway was found to be involved in the process by which FGF20 regulates S100A9 to counteract colitis.</p><p><strong>Conclusions: </strong>These results suggest that FGF20 acts as a negative regulator of S100A9 and NF-κB, thereby inhibiting M1 macrophage polarization and restoring intestinal epithelial barrier integrity in mice with DSS-induced colitis. FGF20 may serve as a potential therapeutic target for the treatment of ulcerative colitis.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101486"},"PeriodicalIF":7.1,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538137","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":"Therapeutic Potential of STE20-Type Kinase STK25 Inhibition for the Prevention and Treatment of Metabolically Induced Hepatocellular Carcinoma.","authors":"Ying Xia, Mara Caputo, Emma Andersson, Bernice Asiedu, Jingjing Zhang, Wei Hou, Manoj Amrutkar, Emmelie Cansby, Nadia Gul, Anne Gemmink, Caitlyn Myers, Mariam Aghajan, Sheri Booten, Andrew J Hoy, Anetta Härtlova, Per Lindahl, Anders Ståhlberg, Gert Schaart, Matthijs K C Hesselink, Andreas Peter, Sue Murray, Margit Mahlapuu","doi":"10.1016/j.jcmgh.2025.101485","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101485","url":null,"abstract":"<p><strong>Background & aims: </strong>Hepatocellular carcinoma (HCC) is a rapidly growing malignancy with high mortality. Recently, metabolic dysfunction-associated steatohepatitis (MASH) has emerged as a major HCC catalyst; however, signals driving transition of MASH to HCC remain elusive and treatment options are limited. Herein, we investigated the role of STE20-type kinase STK25, a critical regulator of hepatocellular lipotoxic milieu and MASH susceptibility, in the initiation and progression of MASH-related HCC.</p><p><strong>Methods: </strong>The clinical relevance of STK25 in HCC was assessed in publicly available datasets and by RT-qPCR and proximity ligation assay in a validation cohort. The functional significance of STK25 silencing in human hepatoma cells was evaluated in vitro and in a subcutaneous xenograft mouse model. The therapeutic potential of STK25 antagonism was examined in a mouse model of MASH-driven HCC, induced by a single diethylnitrosamine injection combined with a high-fat diet.</p><p><strong>Results: </strong>Analysis of public databases and in-house cohorts revealed that STK25 expression in human liver biopsies positively correlated with HCC incidence and severity. The in vitro silencing of STK25 in human hepatoma cells suppressed proliferation, migration, and invasion with efficacy comparable to that achieved by anti-HCC drugs sorafenib or regorafenib. STK25 knockout in human hepatoma cells also blocked tumor formation and growth in a subcutaneous xenograft mouse model. Furthermore, pharmacologic inhibition of STK25 with antisense oligonucleotides-administered systemically or hepatocyte-specifically-efficiently mitigated the development and exacerbation of hepatocarcinogenesis in a mouse model of MASH-driven HCC.</p><p><strong>Conclusion: </strong>This study underscores STK25 antagonism as a promising therapeutic strategy for the prevention and treatment of HCC in the context of MASH.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101485"},"PeriodicalIF":7.1,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538201","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}