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NTN1 cell-autonomously promotes fibrotic response in HSCs

ABSTRACT: Liver fibrosis is a hallmark of progressive liver diseases including metabolic dysfunction-associated steatohepatitis (MASH). Activated hepatic stellate cells (HSCs) are responsible for the excessive synthesis of extracellular matrix(ECM) proteins and collagen deposition in the liver, leading to progressive loss of hepatic functions. However, the nature of paracrine and autocrine signals driving HSC activation and fibrotic response within the liver microenvironment remains incompletely delineated. Here we uncover Netrin-1 (NTN1) as a crucial HSC-derived autocrine factor that promotes HSC activation and liver fibrosis. Hepatic NTN1 mRNA and protein levels were elevated during fibrosis associated with MASH and CCl4-induced liver injury. Hepatic NTN1 overexpression exacerbated diet-induced MASH pathologies and CCl4-induced liver fibrosis. Conversely, HSC-specific conditional ablation of NTN1 alleviated the progression of liver fibrosis. Mechanistic studies using cultured HSCs demonstrated that NTN1 promoted HSC activation in a cell-autonomous manner via a UNC5B and Ca2+-dependent signaling pathway. These findings illustrate the causative role of NTN1-mediated autocrine signaling in driving HSC activation and fibrotic response during liver disease, suggesting potential therapeutic targets for anti-fibrosis therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE285431 | GEO | 2026/02/25

REPOSITORIES: GEO

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NTN1 cell-autonomously promotes fibrotic response in HSCs.

Project description:Liver fibrosis is a hallmark of progressive liver diseases including metabolic dysfunction-associated steatohepatitis (MASH). Activated hepatic stellate cells (HSCs) are responsible for the excessive synthesis of extracellular matrix(ECM) proteins and collagen deposition in the liver, leading to progressive loss of hepatic functions. However, the nature of paracrine and autocrine signals driving HSC activation and fibrotic response within the liver microenvironment remains incompletely delineated. Here we uncover Netrin-1 (NTN1) as a crucial HSC-derived autocrine factor that promotes HSC activation and liver fibrosis. Hepatic NTN1 mRNA and protein levels were elevated during fibrosis associated with MASH and CCl4-induced liver injury. Hepatic NTN1 overexpression exacerbated diet-induced MASH pathologies and CCl4-induced liver fibrosis. Conversely, HSC-specific conditional ablation of NTN1 alleviated the progression of liver fibrosis. Mechanistic studies using cultured HSCs demonstrated that NTN1 promoted HSC activation in a cell-autonomous manner via a UNC5B and Ca2+-dependent signaling pathway. These findings illustrate the causative role of NTN1-mediated autocrine signaling in driving HSC activation and fibrotic response during liver disease, suggesting potential therapeutic targets for anti-fibrosis therapy.

2026-02-25 | GSE303583 | GEO

GDF10 cell-autonomously alleviates fibrotic response in HSCs

Project description:Liver fibrosis has emerged as the primary determinant of outcomes in metabolic dysfunction associated steatohepatitis (MASH). Quiescent hepatic stellate cells (HSCs) differentiate into activated HSCs or myofibroblasts, which drives liver fibrosis and contribute to the progressive loss of hepatic function. However, the underlying mechanisms of autocrine signals driving and reversing HSC activation and fibrotic response within the liver microenvironment remains incompletely delineated. Here, through searching for cytokines highly enriched expression in HSCs compared to other liver cell types by single-cell transcriptomic analysis, we found that Gdf10 is specifically expressed in HSCs, whereas its protein levels were elevated during fibrosis associated with MASH and CCl4-induced liver injury. The functional importance of GDF10 in alleviating the progression of liver fibrosis was demonstrated using gain and loss of GDF10 function mice and cultured HSCs treated with GDF10. Furthermore, the novel HSC-targeted delivery strategy of Gdf10 mRNA in fibrosis mice reversed their fibrotic phenotypes. These results reveal a new regulatory pathway in MASH microenvironment, suggesting a promising strategy for delivering drugs that can shift HSC functions to restore HSC balance.

2025-12-04 | GSE303711 | GEO

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Project description:The mechanisms of hepatic stellate cell (HSC) activation and the development of liver fibrosis remains largely unknow. Here, we revealed a fibrosis related mechanism of hepatocytes-HSCs crosstalk regulated by hepatocyte LONP1. We demonstrate that hepatocyte LONP1 expression is decreased in HFD-fed mice and MASH patients. Liver-specific LONP1 deficiency increases orotic acid level and aggravates MASH-induced liver fibrosis in mice. We have identified DHODH as a substrate that is selectively degraded by LONP1 in an ATP-dependent manner. Moreover, activation of LONP1 reduces orotic acid levels and alleviates MASH-induced fibrosis in mice. Mechanistically, LONP1 mediates DHODH turnover, maintaining lower orotic acid levels to inhibit ATF3-mediated HSC proliferation and activation, thereby preventing liver fibrosis. Furthermore, plasma orotic acid levels are negatively correlated with liver LONP1 levels in humans. Therefore, targeting LONP1-mediated hepatocyte-HSC communication may represent a promising therapeutic strategy for MASH-induced liver fibrosis.

2025-09-23 | PXD055467 | Pride

TGF-β1/p65/MAT2A: a novel pathway involved in the regulation of intracellular SAM and liver fibrogenesis - Part2

Project description:Hepatic stellate cell (HSC) activation induced by transforming growth factor β (TGF-β1) plays a pivotal role in the fibrogenesis. The complex downstream mediators of TGF-β1 are largely unknown. Here, proteomics analysis and biological validation demonstrated that methionine adenosyltransferase 2A (MAT2A) was significantly upregulated in a CCl4-induced fibrosis mice model and a small molecule NPLC0393, known to block TGF-β1/Smad3 signaling, inhibited its upregulation. In HSC cells, TGF-β1 induced elevation of MAT2A and MAT2β expression as well as reduction of S-adenosylmethionine (SAM) content, which further promoted HSC activation. Functionally, in vivo and in vitro knockdown of MAT2A alleviated CCl4- and TGF-β1-induced HSC activation, whereas in vivo overexpression of MAT2A facilitated hepatic fibrosis and abolished therapeutic effect of NPLC0393. TGF-β1 induced p65 phosphorylation and NF-κB activation, thereby promoted the transcription of MAT2A and its protein expression. In addition, overexpression of p65 abrogated NPLC0393 mediated inhibition of HSC activation. This study identified a novel pathway TGF-β1/p65/MAT2A that was involved in the regulation of intracellular SAM contents and liver fibrogenesis, suggesting that this pathway is a potential therapeutic target for hepatic fibrosis.

2019-11-12 | PXD011135 | Pride

TGF-β1/p65/MAT2A: a novel pathway involved in the regulation of intracellular SAM and liver fibrogenesis - Part1

2019-11-12 | PXD011134 | Pride

Multi-Modal Comparison of human Hepatic Stellate Cells identifies novel therapeutic targets for Metabolic Dysfunction-Associated Steatotic Liver Disease

Project description:Background and aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) progresses from steatosis (Metabolic dysfunction-associated steatotic liver, MASL) to Metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis. Activation of Hepatic Stellate Cells (HSCs) into fibrogenic myofibroblasts plays a critical role in the pathogenesis of MASH liver fibrosis. Here we compared gene expression and chromatin accessibility profiles of human HSCs in NORMAL, MASL, and MASH livers at single cell resolution. Methods: 18 human livers were profiled using single-nucleus (sn) RNA-seq and snATAC-seq. High priority targets were identified and then tested in 2D human HSCs, 3D human liver spheroids, and HSC-specific gene knockout mice. Results: This study identified novel gene regulatory mechanisms underlying MASL- and MASH-associated HSC heterogeneity and outlined potential strategies for anti-fibrotic therapy. Specifically, MASH-enriched HSC-subcluster hA1, represented by highly fibrogenic population of myofibroblasts, served as a critical source of extracellular matrix protein (ECM) in MASH, and its activation was regulated via a cross-talk between lineage-specific (JUNB/AP1), cluster-specific (RUNX1/2) and signal-specific (FOXA1/2) transcription factors (TFs). Additionally, we identified a set of core genes (GAS7, SPON1, SERPINE1, LTBP2, KLF9, EFEMP1) that drive ECM production in hA1 HSCs. The pathological relevance of the selected hA1 targets, such as SERPINE1 and others, was demonstrated using siRNA-based HSC-specific gene knockdown or pharmacological inhibitor of SERPINE1 in 3D human MASH liver spheroids, and HSC-specific Serpine1 knockout mice with MASH. Conclusion: We identified potential targets for anti-fibrotic therapy of MASH in patients.

2024-11-13 | GSE244832 | GEO

Mouse hepatocyte conditioned media LC-MS/MS.

Project description:Hepatocyte caspase-8 is elevated in MASH and promotes fibrosis independently of apoptosis changes. To investigate how hepatocyte caspase-8 might drive liver fibrosis progression in MASH, we focused on activated hepatic stellate cells (HSCs), which are the primary source of collagen-producing myofibroblasts and central players in MASH fibrosis. To assess a potential link between hepatocyte caspase-8 and HSC activation, we used an ex vivo model where primary murine HSCs were cultured with conditioned media from siCasp8-treated or control primary hepatocytes. Supporting our hypothesis, HSC activation markers were reduced in HSCs exposed to conditioned media from Casp8-silenced AML12 hepatocytes compared to controls. To pinpoint caspase-8-dependent secretory proteins that could activate HSCs, we conducted LC-MS/MS on conditioned media from these cells, identifying secretory proteins reduced in Casp8-silenced AML12 hepatocytes.

2025-07-09 | PXD057540 | Pride

An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in non-alcoholic steatohepatitis

Project description:Advanced hepatic fibrosis, driven by the activation of hepatic stellate cells (HSCs), affects millions world-wide and is the strongest predictor of mortality in non-alcoholic steatohepatitis (NASH), yet there are no approved anti-fibrotic therapies. To identify novel anti-fibrotic drug targets, we integrated progressive transcriptomic and morphological responses that accompany HSC activation in advanced disease using single nuclear RNA sequencing and tissue clearing in a robust, murine NASH model. In advanced fibrosis, an autocrine HSC signaling circuit emerges that is comprised of 68 receptor-ligand interactions conserved between murine and human NASH. These predicted interactions are supported by the parallel appearance of markedly increased direct stellate cell-cell contacts in murine NASH. As proof of principle, pharmacological inhibition of one such autocrine interaction, NTRK3-NTF3, inhibits human HSC activation in culture and reverses advanced murine NASH-fibrosis in vivo. We have uncovered a novel repertoire of previously uncharacterized anti-fibrotic drug targets underlying advanced fibrosis in vivo. The findings suggest a novel therapeutic paradigm in which stage-specific therapies could yield enhanced anti-fibrotic efficacy in patients with advanced fibrosis.

2022-10-21 | GSE212837 | GEO

Glycolysis in hepatic stellate cells coordinates fibrogenic extracellular vesicle release spatially to amplify liver fibrosis

Project description:Liver fibrosis is characterized by the activation of perivascular hepatic stellate cells (HSCs), the release of fibrogenic nano-sized extracellular vesicles (EVs) and increased HSC glycolysis. Nevertheless, how glycolysis in HSCs coordinates fibrosis amplification through tissue zone-specific pathways remains elusive. Here, we demonstrate that HSC-specific genetic inhibition of glycolysis reduced liver fibrosis. Moreover, spatial transcriptomics revealed a fibrosis-mediated upregulation of EV-related pathways in the liver pericentral zone, which was abrogated by the glycolysis genetic inhibition. Mechanistically, glycolysis in HSCs upregulated the expression of EV-related genes such as RAB31 by enhancing histone-3-lysine-9 acetylation on the promoter region, which increased EV release. Functionally, these glycolysis-dependent EVs increased fibrotic gene expression in recipient HSC. Furthermore, EVs derived from glycolysis-deficient mice abrogated liver fibrosis amplification in contrast to glycolysis-competent mouse EVs. In summary, glycolysis in HSCs amplifies liver fibrosis by promoting fibrogenic EV release in the hepatic pericentral zone, which represents a potential therapeutic target.

2024-05-16 | PXD050337 | Pride

Mannose reduces fructose metabolism and reverses MASH in human liver slices and murine models in vivo

Project description:Background & Aims: Fibrosis drives liver-related mortality in metabolic dysfunction-associated steatohepatitis (MASH), yet we have limited medical therapies to target MASH-fibrosis progression. Here we report that mannose, a simple sugar, attenuates MASH steatosis and fibrosis in two robust murine models and human liver slices. Methods: The well-validated FAT-MASH murine model for liver steatosis and fibrosis was employed. Mannose was supplied in the drinking water at the start (“Prevention” group) or at week 6 of the 12-week MASH regimen (“Therapy” group). The in vivo anti-fibrotic effects of mannose supplementation were tested in a second model of carbon tetrachloride (CCl4)-induced liver fibrosis. A quantitative and automated digital pathology approach was used to comprehensively assess steatosis and fibrosis phenotypes. Mannose was also tested in vitro in human and primary mouse hepatocytes conditioned with free fatty acids alone or with fructose, and Human Precision Cut Liver Slices (hPCLS) from patients with end-stage MASH cirrhosis. Results: Oral mannose supplementation improved liver fibrosis in vivo in both FAT-MASH and CCl4 mouse models, as well as in hPCLS MASH samples. Mannose also reduced liver steatosis in FAT-MASH mice, and in human and mouse hepatocytes in vitro. Ketohexokinase (KHK), the main enzyme in fructolysis, was decreased with mannose in whole mouse liver, cultured hepatocytes, and hPCLS. Removal of fructose or overexpression of KHK each abrogated the anti-steatotic effects of mannose. Conclusions: This study identifies mannose as a novel therapeutic candidate for MASH that mitigates steatosis by dampening hepatocyte KHK expression and exerts independent anti-fibrotic effects in two mouse models and human liver tissue slices.

2025-01-31 | GSE287943 | GEO

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