EphB2 deficiency in hepatic stellate cells mitigated MASH fibrosis in mice.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE274899 | GEO | 2026/01/31
REPOSITORIES: GEO
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Project description:Metabolic dysfunction-associated steatohepatitis (MASH) is emerging as the leading cause for liver transplantation worldwide. MASH is chatacterized by hepatic lipid accumulation, inlammation and fibrosis which is associaed with worst outcome in patients sufferring from this pathology. Using the Gubra Amyln NASH (GAN) diet model of murine MASH, we showed that global deletion of Ephb2 in mice protect them from GAN diet-induced inlammation and fibrosis. EphB2 could be a potential therapeutic target for the treatment of MASH fibrosis.
2026-01-31 | GSE274897 | GEO
Project description:EphB2 deficiency in hepatic stellate cells mitigated MASH fibrosis in mice.
| PRJNA1148426 | ENA
Project description:Hepatic stellate cells (HSCs) are the major effector cell-type responsible for the production of collagens in hepatic fibrogenesis. In this study we showed that when EPHB2 is silenced in human primary HSCs, they become refractory to TGFbeta-induced-HSCs-to-myofibroblasts transdifferentiation. More importantly, EphB2-specific deletion in HSCs using the tamoxifen inducible PdgfCre-eRT2 promoer driver is sufficient to mitigate MASH fibrosis in mice.
2026-01-31 | GSE274898 | GEO
Project description:The receptor tyrosine kinase EphB2 promotes MASH fibrosis in mice.
| PRJNA1148424 | ENA
Project description:Objectives: Eph/Ephrin cell-cell signaling is emerging as a key player in tissue fibrogenesis. The aim of this study was to test the hypothesis that the receptor tyrosine kinase EphB2 mediates dermal fibrosis in systemic sclerosis (SSc). Methods: We assessed normal and SSc human skin biopsies for EphB2 expression. The in vivo role of EphB2 in skin fibrosis was investigated by subjecting EphB2-knockout mice to both bleomycin-induced and tight skin (Tsk1/+) genetic mouse models. EphB2 kinase-dead and overactive point mutant mice were used to evaluate the role of EphB2 forward signaling in bleomycin-induced dermal fibrosis. In vitro studies were performed on dermal fibroblasts from SSc patients and healthy controls, which was followed by in vivo analysis of fibroblast-specific EphB2 deficient mice. Results: Expression of EphB2 is upregulated in SSc skin tissue and explanted SSc dermal fibroblasts compared to healthy controls. EphB2 expression is elevated in two animal models of dermal fibrosis. In mice, EphB2 drives dermal fibrosis in both the bleomycin and the Tsk1/+ models of skin fibrosis. EphB2 forward signaling is a critical mediator of dermal fibrosis. Transforming growth factor-β (TGFβ) cytokines upregulate EphB2 in dermal fibroblasts via non-canonical TGFβ/SMAD signaling and silencing EphB2 in dermal fibroblasts is sufficient to dampen TGFβ-induced fibroblast-to-myofibroblast differentiation. Moreover, mice with fibroblast-specific deletion of EphB2 showed impaired fibroblast-to-myofibroblast differentiation and reduced skin fibrosis upon bleomycin challenge. Conclusion: Our data implicate EphB2 overexpression and kinase-mediated forward signaling in the development of dermal fibrosis in SSc. EphB2 thus represents a potential new therapeutic target for SSc.
2024-04-10 | GSE253089 | GEO
Project description:Cytochrome P450 (CYP) monooxygenases (predominately the CYP2C and CYP2J isoforms) catalyze the oxidative metabolism of polyunsaturated fatty acids to generate epoxy fatty acids (EpFAs) and fatty acid diols, which are bioactive lipid signaling molecules that regulate inflammation and other important biological processes. Animal and human studies suggest that this pathway is dysregulated in metabolic dysfunction-associated steatohepatitis (MASH) and related liver diseases; however, its functional role in disease development of MASH, especially liver fibrosis, remains poorly understood. Here, we investigated the role of CYP2C29, the predominant CYP2C/2J isoform in mouse livers, in a choline-deficient, L-amino acid–defined, high-fat diet (CDAA-HFD)-induced liver fibrosis model. Compared with wild-type (WT) mice, CYP2C29 knockout (KO) mice exhibited reduced hepatic concentrations of CYP-derived EpFAs and fatty acid diols and attenuated development of liver fibrosis. Transcriptomic analysis further revealed that Cyp2c29 disruption suppressed the hepatic expression of multiple pro-fibrogenic, pro-inflammatory, and pro-angiogenic genes. Together, these findings demonstrate that the CYP monooxygenase pathway promotes the development of CDAA-HFD-induced liver fibrosis and its associated disorders.
2025-11-24 | GSE311044 | GEO
Project description:Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease characterized by steatosis, inflammation, and fibrosis. However, the mechanisms linking lipid droplet (LD) metabolism to MASH progression remain poorly understood. AF6 is a polarity protein known to regulate metabolic homeostasis, but its role in the development of MASH remains largely undefined. Here, we identify AF6 as a critical regulator of hepatic lipid accumulation and inflammation in MASH. Hepatic AF6 expression is elevated in MASH patients and diet-induced mouse models. Liver-specific deletion of AF6 attenuated steatosis, inflammation, and fibrosis in both high-fat, high-cholesterol (HFHC) and choline-deficient, amino acid-defined high-fat diet (CDA-HFD)-induced MASH models. Mechanistically, lipid overload promotes nuclear translocation of AF6, which interacts with the transcription factor C/EBPβ and enhances its nuclear accumulation. This interaction increases transcription of the lipid droplet fusion protein CIDEA, promoting LD growth and lipid deposition. AF6 also exacerbates MASH by enhancing C/EBPβ-mediated proinflammatory signaling. Restoration of CIDEA expression in AF6-deficient mice reverses the protective effects. In human liver biopsies and iPSC-derived liver organoids, the AF6–C/EBPβ–CIDEA axis is upregulated and correlates with disease severity. Importantly, a CRISPR-Cas9–based lipid nanoparticle (LNP) therapy targeting AF6 effectively reduced lipid accumulation, inflammation, and fibrosis in MASH mice and organoids. AF6 promotes MASH progression by facilitating C/EBPβ nuclear localization and transcriptional activation of CIDEA. Targeting the AF6–C/EBPβ–CIDEA axis represents a promising therapeutic strategy for treating MASH.
2026-02-18 | GSE305662 | GEO
Project description:Current therapeutic strategies for treating non-alcoholic steatohepatitis (NASH) have failed to alleviate liver fibrosis, which is a devastating feature leading to hepatic dysfunction. Here, we integrated single-nucleus transcriptomics and epigenomics to characterize all major liver cell types during NASH development in mice and humans. The bifurcation of hepatocyte trajectory with NASH progression was conserved between mouse and human. At the non-alcoholic fatty liver (NAFL) stage, hepatocytes exhibited metabolic adaptation, whereas at the NASH stage, a subset of hepatocytes was enriched for the signatures of cell adhesion and migration, which was mainly demarcated by receptor tyrosine kinase EphB2. EphB2, acting as a downstream effector of Notch signaling in hepatocytes, was sufficient to induce cell-autonomously inflammation. Knockdown of Ephb2 in hepatocytes ameliorated inflammation and fibrosis in NASH. Thus, EphB2 expressing hepatocytes contribute to NASH progression and may serve as a potential therapeutic target.
2023-02-08 | GSE189600 | GEO
Project description:Excess cholesterol accumulation contributes to fibrogenesis in metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis [NASH]), but how hepatic cholesterol metabolism becomes dysregulated in MASH is not completely understood. We show here that human fibrotic MASH livers have decreased EHBP1, a novel GWAS locus associated with LDL cholesterol, and that the EHBP1 rs10496099 T>C variant in MASH patients is associated with decreased hepatic EHBP1 expression and with augmented MASH fibrosis. Congruent with the human data, EHBP1 loss- and gain-of-function increases and decreases MASH fibrosis in mice, respectively. Mechanistic studies reveal that EHBP1 promotes sortilin (SORT1)-mediated PCSK9 secretion, leading to LDLR degradation, decreased LDL uptake, and reduced TAZ, a fibrogenic effector. At a cellular level, EHBP1 deficiency affects intracellular localization of retromer, a protein complex required for sortilin stabilization. Our novel therapeutic approach to stabilizing retromer is effective in mitigating MASH fibrosis. Moreover, we show that the TNFα/PPARα pathway suppresses EHBP1 in MASH. These data not only provide new mechanistic insight into the role of EHBP1 in cholesterol metabolism and MASH fibrosis by uncovering the interaction between EHBP1 and other cholesterol-related loci, including SORT1, PCSK9, and LDLR, but also elucidate a novel interplay between inflammation and EHBP1-mediated cholesterol metabolism.
2025-01-23 | GSE232780 | GEO
Project description:Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease associated with hepatic inflammation and fibrosis. Inflammasome-mediated IL-18 signaling is enhanced under MASH condition. IL-18 binding protein (IL-18BP) is a soluble protein that can block IL-18 actions and therapeutic potential of IL-18BP for MASH-induced fibrosis is largely unknown. We newly developed a human IL-18BP biologics (APB-R3) and injected it to mice to evaluate its pharmacologic efficacy. APB-R3 strikingly abolished hepatic fibrosis and reduced collagen markers. We further investigated whether APB-R3 could inhibit fibrotic activation of hepatic stellate cells (HSCs). This study proposes that abrogation of IL-18 signaling by boosting IL-18BP can strongly inhibit the development of MASH-induced fibrosis and our engineered IL-18BP biologics can become promising therapeutic candidate for curing MASH.
2024-10-18 | GSE279496 | GEO