Pub Date : 2025-09-29DOI: 10.1016/j.jcmgh.2025.101653
Lan Xiao , Song Ah Chae , Dongyoon Yoo , Hee K. Chung , Min S. Kwon , Amy VanderStoep , Ting-Xi Yu , Bridgette Warner , Myriam Gorospe , Jian-Ying Wang
Background & Aims
Long noncoding RNA uc.173, transcribed from ultraconserved regions, modulates many cell processes central to human pathologies, but the mechanism underlying uc.173 in the homeostasis of the intestinal epithelium is underexplored. Here, we investigated the role of uc.173 in regulating mitochondrial metabolism and defined the implication of altered mitochondrial activity by uc.173 in renewal of the intestinal mucosa.
Methods
Studies were conducted in CRISPR-Cas9 knock-in mice, primary enterocytes, and Caco-2 cells. Mitochondrial structure and function were elucidated by measuring mitochondria-associated proteins and mitochondrial respiratory capacity. Intestinal mucosal growth was measured by Ki67 immunostaining or BrdU incorporation assays.
Results
Transient and specific deletion of uc.173 in the intestinal epithelium of mice by CRISPR-Cas9 knock-in using small guide RNA decreased the levels of several mitochondria-associated proteins including PGC-1α, along with disrupted mucosal growth. Decreasing the levels of uc.173 in cultured intestinal epithelial cells also decreased mitochondrial proteins and caused defects in the mitochondrial respiratory capacity. Reinforcing mitochondrial activity by using a mitochondrial activator or by overexpressing PGC-1α rescued growth of uc.173-deficient intestinal organoids. Mechanistic studies revealed that uc.173 increased PGC-1α expression by acting as a molecular decoy for miR-29b, thereby preventing the repressive interaction of miR-29b with PGC-1α mRNA.
Conclusions
These findings indicate that uc.173 is a novel regulator of mitochondrial metabolism in the intestinal epithelium and highlight a role of deregulation of uc.173, miR-29b, and PGC-1α in the suppressed renewal of intestinal mucosa in patients with critical illnesses.
{"title":"Long Noncoding RNA uc173 is a Novel Regulator of Mitochondrial Metabolism Driving Intestinal Mucosal Growth","authors":"Lan Xiao , Song Ah Chae , Dongyoon Yoo , Hee K. Chung , Min S. Kwon , Amy VanderStoep , Ting-Xi Yu , Bridgette Warner , Myriam Gorospe , Jian-Ying Wang","doi":"10.1016/j.jcmgh.2025.101653","DOIUrl":"10.1016/j.jcmgh.2025.101653","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Long noncoding RNA <em>uc.173</em>, transcribed from ultraconserved regions, modulates many cell processes central to human pathologies, but the mechanism underlying <em>uc.173</em> in the homeostasis of the intestinal epithelium is underexplored. Here, we investigated the role of <em>uc.173</em> in regulating mitochondrial metabolism and defined the implication of altered mitochondrial activity by <em>uc.173</em> in renewal of the intestinal mucosa.</div></div><div><h3>Methods</h3><div>Studies were conducted in CRISPR-Cas9 knock-in mice, primary enterocytes, and Caco-2 cells. Mitochondrial structure and function were elucidated by measuring mitochondria-associated proteins and mitochondrial respiratory capacity. Intestinal mucosal growth was measured by Ki67 immunostaining or BrdU incorporation assays.</div></div><div><h3>Results</h3><div>Transient and specific deletion of <em>uc.173</em> in the intestinal epithelium of mice by CRISPR-Cas9 knock-in using small guide RNA decreased the levels of several mitochondria-associated proteins including PGC-1α, along with disrupted mucosal growth. Decreasing the levels of <em>uc.173</em> in cultured intestinal epithelial cells also decreased mitochondrial proteins and caused defects in the mitochondrial respiratory capacity. Reinforcing mitochondrial activity by using a mitochondrial activator or by overexpressing PGC-1α rescued growth of <em>uc.173</em>-deficient intestinal organoids. Mechanistic studies revealed that <em>uc.173</em> increased PGC-1α expression by acting as a molecular decoy for miR-29b, thereby preventing the repressive interaction of miR-29b with <em>PGC-1α</em> mRNA.</div></div><div><h3>Conclusions</h3><div>These findings indicate that <em>uc.173</em> is a novel regulator of mitochondrial metabolism in the intestinal epithelium and highlight a role of deregulation of <em>uc.173</em>, miR-29b, and PGC-1α in the suppressed renewal of intestinal mucosa in patients with critical illnesses.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 2","pages":"Article 101653"},"PeriodicalIF":7.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208284","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}
Pub Date : 2025-09-29DOI: 10.1016/j.jcmgh.2025.101651
Zhe Yang , Niujian Wu , Xin Li , Yun Li , Zhanjin Lu , Taoping Sun , Zhixing Cao , Xianghong Wang , Chen Yang , Shisong Han , Hongyun Lu
Background & Aims
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.
Methods
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.
Results
Compared with their wild-type littermates, hepatocyte-specific HIF-2α knockout mice exhibited a substantial reduction in high-fat diet-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 free fatty acids challenge. Mechanistically, HIF-2 directly bound to the promoter region of protein kinase RNA-like ER kinase, leading to the activation of the activating transcription factor 4 signaling under metabolic stress, thereby aggravating lipogenesis while inhibiting lipid oxidation in hepatocytes.
Conclusions
These data indicate that HIF-2α acts as a contributing factor to MASLD progression via activating transcription factor 4 signaling.
{"title":"HIF-2α-driven Lipogenesis and Inflammation in Metabolic Dysfunction-associated Steatotic Liver Disease: 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":"10.1016/j.jcmgh.2025.101651","url":null,"abstract":"<div><h3>Background & Aims</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>Compared with their wild-type littermates, hepatocyte-specific HIF-2α knockout mice exhibited a substantial reduction in high-fat diet-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 free fatty acids challenge. Mechanistically, HIF-2 directly bound to the promoter region of protein kinase RNA-like ER kinase, leading to the activation of the activating transcription factor 4 signaling under metabolic stress, thereby aggravating lipogenesis while inhibiting lipid oxidation in hepatocytes.</div></div><div><h3>Conclusions</h3><div>These data indicate that HIF-2α acts as a contributing factor to MASLD progression via activating transcription factor 4 signaling.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 2","pages":"Article 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}
Pub Date : 2025-09-29DOI: 10.1016/j.jcmgh.2025.101652
Jiali Xu , Qing Ji , Yining Chen , Yu Xu , Zhihui Wang , Zhenyu Yuan , Dapeng Gao , Lidong Zhang , Cunming Liu , Qing Li , Liren Zhang , Jingjing Dai
Background & Aims
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.
Methods
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, 3-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.
Results
Our data reveal that etomidate suppresses programmed death-ligand 1 (PD-L1) expression in HCC cells, thereby potentiating antitumor immunity. Mechanistically, etomidate inhibits the Janus kinase 2/signal transducer and activator of transcription 3 axis in tumor cells, leading to reduced PD-L1 transcription and increased infiltration and activation of cytotoxic CD8+ T lymphocytes.
Conclusions
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.
{"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":"10.1016/j.jcmgh.2025.101652","url":null,"abstract":"<div><h3>Background & Aims</h3><div>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.</div></div><div><h3>Methods</h3><div>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, 3-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.</div></div><div><h3>Results</h3><div>Our data reveal that etomidate suppresses programmed death-ligand 1 (PD-L1) expression in HCC cells, thereby potentiating antitumor immunity. Mechanistically, etomidate inhibits the Janus kinase 2/signal transducer and activator of transcription 3 axis in tumor cells, leading to reduced <em>PD-L1</em> transcription and increased infiltration and activation of cytotoxic CD8<sup>+</sup> T lymphocytes.</div></div><div><h3>Conclusions</h3><div>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.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 2","pages":"Article 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}
Pub Date : 2025-09-26DOI: 10.1016/j.jcmgh.2025.101648
Randy S. Longman
{"title":"Cell Adhesion Molecule 1 Emerges as a Biomarker and Therapeutic Opportunity in Inflammatory Bowel Disease","authors":"Randy S. Longman","doi":"10.1016/j.jcmgh.2025.101648","DOIUrl":"10.1016/j.jcmgh.2025.101648","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 1","pages":"Article 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}
Pub Date : 2025-09-24DOI: 10.1016/j.jcmgh.2025.101642
Melanie Scharr , Simon Scherer , Jörg Fuchs , Bernhard Hirt , Peter H. Neckel
Background & Aims
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).
Methods
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 fluorescence-activated cell sorting-based in vitro assays to stratify human ENS cells for LGR receptor expression, and to characterize them by immunofluorescence colabeling studies in vivo.
Results
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), whereas 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.
Conclusions
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.
{"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":"10.1016/j.jcmgh.2025.101642","url":null,"abstract":"<div><h3>Background & Aims</h3><div>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).</div></div><div><h3>Methods</h3><div>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 fluorescence-activated cell sorting-based in vitro assays to stratify human ENS cells for LGR receptor expression, and to characterize them by immunofluorescence colabeling studies in vivo.</div></div><div><h3>Results</h3><div>If applied to murine and human ENS progenitors, RSPO1 led to an increased proliferation (<em>P</em> = .002), followed by enhanced enteric neurogenesis (<em>P</em> < .001). This coincided with an upregulation of LGR4 expression during ENS progenitor proliferation (<em>P ≤</em> .001) in vitro. In contrast, we observed a reduced proliferation in ENS progenitors expressing LGR5 (<em>P</em> ≤ .001), whereas LGR6 was not expressed by proliferative ENS progenitors (<em>P</em> ≤ .05). Instead, LGR5 and LGR6 expression increased over the course of induced neuronal differentiation (LGR5: <em>P</em> ≤ .001 and LGR6: <em>P</em> ≤ .05), consistent with the in vivo expression.</div></div><div><h3>Conclusions</h3><div>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.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 2","pages":"Article 101642"},"PeriodicalIF":7.1,"publicationDate":"2025-09-24","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}
Pub Date : 2025-09-24DOI: 10.1016/j.jcmgh.2025.101637
Xuzhen Yan , Qi Han , Yiwen Wang , Weiyu Li , Ning Zhang , Xu Fan , Wei Chen , Hong You , Aiting Yang
Background & Aims
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. Although 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 lysyl oxidase-like 1 (LOXL1), a pivotal enzyme in ECM cross-linking, in crosstalk between HSCs and LSECs during liver fibrosis.
Methods
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 quantitative polymerase chain reaction (qPCR). Liver tissue and HSCs were analyzed by RNA sequencing to study LOXL1’s mechanisms regulating liver fibrosis.
Results
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 RUNX family transcription factor 1 (RUNX1) was implicated in HSC activation and LOXL1-mediated angiogenesis. We propose that LOXL1 enhances HSC activation and LSEC capillarization through the RUNX 1/vascular endothelial growth factor A 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/vascular endothelial growth factor A axis offers a promising therapeutic strategy for liver fibrosis.
{"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":"10.1016/j.jcmgh.2025.101637","url":null,"abstract":"<div><h3>Background & Aims</h3><div>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. Although 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 lysyl oxidase-like 1 (LOXL1), a pivotal enzyme in ECM cross-linking, in crosstalk between HSCs and LSECs during liver fibrosis.</div></div><div><h3>Methods</h3><div>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 (CCl<sub>4</sub>) exposure. Liver samples were assessed by histology, scanning electron microscopy, immunostaining, and quantitative polymerase chain reaction (qPCR). Liver tissue and HSCs were analyzed by RNA sequencing to study LOXL1’s mechanisms regulating liver fibrosis.</div></div><div><h3>Results</h3><div>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 CCl<sub>4</sub>-exposed mice. Our RNA sequencing data, corroborated by public database analyses, indicated RUNX family transcription factor 1 (RUNX1) was implicated in HSC activation and LOXL1-mediated angiogenesis. We propose that LOXL1 enhances HSC activation and LSEC capillarization through the RUNX 1/vascular endothelial growth factor A signaling axis</div></div><div><h3>Conclusions</h3><div>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/vascular endothelial growth factor A axis offers a promising therapeutic strategy for liver fibrosis.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 2","pages":"Article 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}
Pub Date : 2025-09-23DOI: 10.1016/j.jcmgh.2025.101645
Xinzhi Li , Xiaobing Xu , Wenjie Lai , Ai Jiang , Na Zhou , Ying Yu
Prostanoids typically refer to prostaglandins, prostacyclin, and thromboxane, and are a series of bioactive lipid mediators primarily derived from arachidonic acid. Prostanoids play pivotal roles in various physiological processes, including liver repair and regeneration. Liver cells can produce different prostanoids, which can regulate multifaced functions in metabolic homeostasis, liver regeneration, and injury protection, through autocrine and paracrine mechanisms, preferably with the activation of specific receptors. Prostanoids orchestrate a complex network of cellular responses that promote liver repair and regeneration while modulating DNA replication, cellular proliferation, and hepatic inflammation. We reviewed prostanoid biosynthesis and intercellular interactions mediated by prostanoid receptors in the liver, focusing on their involvements in key signaling pathways that govern liver regeneration in response to partial hepatectomy, ischemia/reperfusion injury, and hepatotoxin/immunogen-induced damages. This review underscores the importance of prostanoids in liver homeostasis and highlights potential strategies for manipulating these pathways to improve clinical outcomes in liver repair and regeneration.
{"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":"10.1016/j.jcmgh.2025.101645","url":null,"abstract":"<div><div>Prostanoids typically refer to prostaglandins, prostacyclin, and thromboxane, and are a series of bioactive lipid mediators primarily derived from arachidonic acid. Prostanoids play pivotal roles in various physiological processes, including liver repair and regeneration. Liver cells can produce different prostanoids, which can regulate multifaced functions in metabolic homeostasis, liver regeneration, and injury protection, through autocrine and paracrine mechanisms, preferably with the activation of specific receptors. Prostanoids orchestrate a complex network of cellular responses that promote liver repair and regeneration while modulating DNA replication, cellular proliferation, and hepatic inflammation. We reviewed prostanoid biosynthesis and intercellular interactions mediated by prostanoid receptors in the liver, focusing on their involvements in key signaling pathways that govern liver regeneration in response to partial hepatectomy, ischemia/reperfusion injury, and hepatotoxin/immunogen-induced damages. This review underscores the importance of prostanoids in liver homeostasis and highlights potential strategies for manipulating these pathways to improve clinical outcomes in liver repair and regeneration.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 1","pages":"Article 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}
Pub Date : 2025-09-23DOI: 10.1016/j.jcmgh.2025.101636
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
Background & Aims
Although anti-tumor necrosis factor (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 nonresponse are unknown but are likely multifactorial. Here, we examined myeloid cells expressing signal regulatory protein α (SIRPα) for their potential role in refractory CD.
Methods
Response to anti-TNF was defined as having reached endoscopic and histological healing, whereas nonresponders 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.
Results
Among the CD phenotypes, patients with anti-TNF refractory CD 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 proinflammatory transcriptome, with increased levels of interleukin (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 patients with refractory CD 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.
Conclusions
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.
{"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":"10.1016/j.jcmgh.2025.101636","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Although anti-tumor necrosis factor (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 nonresponse are unknown but are likely multifactorial. Here, we examined myeloid cells expressing signal regulatory protein α (SIRPα) for their potential role in refractory CD.</div></div><div><h3>Methods</h3><div>Response to anti-TNF was defined as having reached endoscopic and histological healing, whereas nonresponders 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<sup>+</sup> cells.</div></div><div><h3>Results</h3><div>Among the CD phenotypes, patients with anti-TNF refractory CD had the highest levels of CD33<sup>+</sup>HLA-DR<sup>+</sup>CD11c<sup>+</sup>SIRPα<sup>+</sup> cells in their intestinal mucosa, but the levels in peripheral blood were unchanged. SIRPα<sup>+</sup> cells from the gut displayed a higher proinflammatory transcriptome, with increased levels of interleukin (IL)-6, TNFα, p40, and IL-1β expression. When isolated and stimulated in vitro with flagellin, these SIRPα<sup>+</sup> cells showed a more pro-inflammatory transcriptome during CD47 ligation than with an IgG control. Moreover, the secretomes of flagellin/CD47-stimulated SIRPα<sup>+</sup> cells from patients with refractory CD 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.</div></div><div><h3>Conclusions</h3><div>Increased levels of myeloid lineage expressing CD33<sup>+</sup>HLA-DR<sup>+</sup>CD11c<sup>+</sup>SIRPα<sup>+</sup> cells in the intestinal mucosa negatively impact epithelial cell function, possibly explaining one mechanism for anti-TNF resistance. The abundance of mucosal SIRPα<sup>+</sup> cells should be further explored as a biomarker and therapeutic target.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 1","pages":"Article 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}
Pub Date : 2025-09-22DOI: 10.1016/j.jcmgh.2025.101638
Steven J. Wilhelm , Grace E. Curry , Neel Matiwala , Jianguo Lin , Tran Quach , Mark.E. Lowe , Miklós Sahin-Tóth , Xunjun K. Xiao
Background & Aims
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.
Methods
We conducted a comprehensive analysis of mice aged 1 to 6 months using histology, immunohistochemistry, protein immunoblotting, quantitative polymerase chain reaction (qPCR), transmission electron microscopy (TEM), and RNA sequencing (RNA-seq) analysis to characterize pancreatic pathological changes.
Results
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 with Pnlip T221M mice, and heterozygous mice showed slower CP development than homozygotes. Both mutant proteins misfolded in the pancreas, inducing endoplasmic reticulum 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 upregulated 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.
Conclusions
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.
{"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":"10.1016/j.jcmgh.2025.101638","url":null,"abstract":"<div><h3>Background & Aims</h3><div>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, <em>CPA1</em> N256K and <em>PNLIP</em> T221M, recapitulate the human CP phenotype. We hypothesized that both models develop CP through similar disease mechanisms.</div></div><div><h3>Methods</h3><div>We conducted a comprehensive analysis of mice aged 1 to 6 months using histology, immunohistochemistry, protein immunoblotting, quantitative polymerase chain reaction (qPCR), transmission electron microscopy (TEM), and RNA sequencing (RNA-seq) analysis to characterize pancreatic pathological changes.</div></div><div><h3>Results</h3><div>Both homozygous models exhibited CP hallmarks, including progressive acinar cell loss, inflammation, fibrosis, and fatty replacement. CP progression was slower and less severe in <em>Cpa1</em> N256K mice compared with <em>Pnlip</em> T221M mice, and heterozygous mice showed slower CP development than homozygotes. Both mutant proteins misfolded in the pancreas, inducing endoplasmic reticulum 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 upregulated 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.</div></div><div><h3>Conclusions</h3><div>Our study demonstrates that <em>Cpa1</em> N256K and <em>Pnlip</em> 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.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 2","pages":"Article 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}
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