Liver Single-Cell Atlas of MASH and Fibrosis Models in Mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE300744 | GEO | 2026/06/18
REPOSITORIES: GEO
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Project description:Immune checkpoint inhibitors (ICIs) show variable efficacy in hepatocellular carcinoma (HCC) depending on etiology. In metabolic dysfunction-associated steatohepatitis (MASH), PD-1+ CD8+ T cells may paradoxically drive liver injury. We investigated whether PD-1 blockade exacerbates liver fibrosis in a non-neoplastic MASH environment. Male C57BL/6J mice were fed a high-fat diet (HFD) for 18 weeks, with weekly carbon tetrachloride (CCl4) during the final 12 weeks. Mice received anti-PD-1 antibody or isotype control every 3 days during the HFD/CCl4 phase. Liver injury, immune cell accumulation, and fibrosis were evaluated via biochemistry, histology, flow cytometry, and transcriptomic analysis. The HFD/CCl4 model exhibited significant hepatic accumulation of PD-1+ CD8+ T cells. PD-1 blockade increased AST/ALT and LDH levels, alongside heightened necroinflammation. Transcriptomic analysis showed upregulation of exhaustion-associated and cytotoxicity-related genes. Histologically, anti-PD-1 treatment was associated with periportal accumulation of F4/80+ macrophages and increased collagen deposition. Notably, we observed close spatial proximity between F4/80+ macrophages and α-smooth muscle actin+ myofibroblasts, suggesting a pro-fibrotic immune-stromal axis. PD-1 inhibition aggravates liver injury and accelerates fibrosis in this MASH model. These findings suggest that PD-1 blockade may provoke unintended pathological consequences in the context of chronic metabolic liver injury.
2026-06-02 | GSE331440 | GEO
Project description:Metabolic dysfunction-associated steatohepatitis (MASH) and its progression to hepatocellular carcinoma remain major clinical challenges. Chronic endoplasmic reticulum (ER) stress, induced by sustained high-fat diet (HFD) intake, promotes hepatic inflammation, lipid accumulation, and hepatocellular dysfunction during MASH pathogenesis. While transcriptional responses are well-characterized, the post-transcriptional mechanisms underlying hepatocyte adaptation to chronic ER stress remain poorly understood. Using an integrative approach combining transcriptomics, ribosome profiling, cytoplasmic polyadenylation analysis, and cis-regulatory mapping, we define the post-transcriptional landscape induced by chronic HFD exposure. To delineate the specific role of chronic ER stress, we use a hepatocyte-specific knockout of a key regulator of translational control under prolonged ER stress. We show that ~70% of HFD-induced gene expression changes are modulated at the translational level. A distinct subset of mRNAs - enriched in suboptimal codons and bearing short poly(A) tails under normal diet - becomes selectively activated upon HFD-induced poly(A) tail elongation. These transcripts, associated with cell cycle, immune response, fibrosis, and tissue remodeling, correlate with MASH severity in both murine models and human samples. Their regulation is mediated by cis-elements in the 3' UTR that coordinate polyadenylation and deadenylation. Loss of this adaptive response exacerbates liver damage and tumor burden in HFD-fed mice.
2026-03-05 | E-MTAB-16293 | biostudies-arrayexpress
Project description:Metabolic dysfunction-associated steatohepatitis (MASH) and its progression to hepatocellular carcinoma remain major clinical challenges. Chronic endoplasmic reticulum (ER) stress, induced by sustained high-fat diet (HFD) intake, promotes hepatic inflammation, lipid accumulation, and hepatocellular dysfunction during MASH pathogenesis. While transcriptional responses are well-characterized, the post-transcriptional mechanisms underlying hepatocyte adaptation to chronic ER stress remain poorly understood. Using an integrative approach combining transcriptomics, ribosome profiling, cytoplasmic polyadenylation analysis, and cis-regulatory mapping, we define the post-transcriptional landscape induced by chronic HFD exposure. To delineate the specific role of chronic ER stress, we use a hepatocyte-specific knockout of a key regulator of translational control under prolonged ER stress. We show that ~70% of HFD-induced gene expression changes are modulated at the translational level. A distinct subset of mRNAs - enriched in suboptimal codons and bearing short poly(A) tails under normal diet - becomes selectively activated upon HFD-induced poly(A) tail elongation. These transcripts, associated with cell cycle, immune response, fibrosis, and tissue remodeling, correlate with MASH severity in both murine models and human samples. Their regulation is mediated by cis-elements in the 3'UTR that coordinate polyadenylation and deadenylation. Loss of this adaptive response exacerbates liver damage and tumor burden in HFD-fed mice.
2026-03-05 | E-MTAB-16295 | biostudies-arrayexpress
Project description:Metabolic dysfunction-associated steatohepatitis (MASH) and its progression to hepatocellular carcinoma remain major clinical challenges. Chronic endoplasmic reticulum (ER) stress, induced by sustained high-fat diet (HFD) intake, promotes hepatic inflammation, lipid accumulation, and hepatocellular dysfunction during MASH pathogenesis. While transcriptional responses are well-characterized, the post-transcriptional mechanisms underlying hepatocyte adaptation to chronic ER stress remain poorly understood. Using an integrative approach combining transcriptomics, ribosome profiling, cytoplasmic polyadenylation analysis, and cis-regulatory mapping, we define the post-transcriptional landscape induced by chronic HFD exposure. To delineate the specific role of chronic ER stress, we use a hepatocyte-specific knockout of a key regulator of translational control under prolonged ER stress. We show that ~70% of HFD-induced gene expression changes are modulated at the translational level. A distinct subset of mRNAs - enriched in suboptimal codons and bearing short poly(A) tails under normal diet - becomes selectively activated upon HFD-induced poly(A) tail elongation. These transcripts, associated with cell cycle, immune response, fibrosis, and tissue remodeling, correlate with MASH severity in both murine models and human samples. Their regulation is mediated by cis-elements in the 3' UTR that coordinate polyadenylation and deadenylation. Loss of this adaptive response exacerbates liver damage and tumor burden in HFD-fed mice.
2026-03-05 | E-MTAB-16294 | biostudies-arrayexpress
Project description:Metabolic dysfunction-associated steatohepatitis (MASH) and its progression to hepatocellular carcinoma remain major clinical challenges. Chronic endoplasmic reticulum (ER) stress, induced by sustained high-fat diet (HFD) intake, promotes hepatic inflammation, lipid accumulation, and hepatocellular dysfunction during MASH pathogenesis. While transcriptional responses are well-characterized, the post-transcriptional mechanisms underlying hepatocyte adaptation to chronic ER stress remain poorly understood. Using an integrative approach combining transcriptomics, ribosome profiling, cytoplasmic polyadenylation analysis, and cis-regulatory mapping, we define the post-transcriptional landscape induced by chronic HFD exposure. To delineate the specific role of chronic ER stress, we use a hepatocyte-specific knockout of a key regulator of translational control under prolonged ER stress. We show that ~70% of HFD-induced gene expression changes are modulated at the translational level. A distinct subset of mRNAs - enriched in suboptimal codons and bearing short poly(A) tails under normal diet - becomes selectively activated upon HFD-induced poly(A) tail elongation. These transcripts, associated with cell cycle, immune response, fibrosis, and tissue remodeling, correlate with MASH severity in both murine models and human samples. Their regulation is mediated by cis-elements in the 3' UTR that coordinate polyadenylation and deadenylation. Loss of this adaptive response exacerbates liver damage and tumor burden in HFD-fed mice.
2026-03-05 | E-MTAB-16346 | biostudies-arrayexpress
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
Project description:Modulation of metabolic, inflammatory, and fibrotic pathways by semaglutide in metabolic dysfunction-associated steatohepatitis Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease strongly associated with cardiometabolic risk factors. Semaglutide, a glucagon-like peptide-1 receptor agonist, improves liver histology in MASH, but the underlying signals and pathways driving semaglutide-induced MASH resolution are not well understood. We show that, in two preclinical MASH models, semaglutide improved histological markers of fibrosis and inflammation, and reduced hepatic expression of fibrosis- and inflammation-related gene pathways.
2025-04-25 | GSE294629 | 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:Background and aims: The incidence of metabolic dysfunction-associated steatohepatitis (MASH) and associated liver fibrosis is rapidly increasing, while pharmacological treatment options remain limited. Despite great efforts in developing novel MASH therapeutics, many investigative therapeutics that reduced fibrosis in preclinical models ultimately lacked efficacy in clinical trials. Therefore, we explored the possibility to predict the efficacy of investigative therapeutics on fibrogenic drive in the early stages of disease development and before effects on pathology become evident. Methods: Ldlr-/-.Leiden mice were fed a high-fat diet (HFD) to induce obesity and MASH. Mice were subsequently treated for four weeks with various therapeutics with established efficacy (obeticholic acid) or lack of efficacy (cenicriviroc, pioglitazone) to study their anti-fibrotic potential. Next, expression of a fibrogenic gene signature was evaluated, which predicts profibrotic processes preceding histopathologic fibrosis. The predictions were validated in parallel with a long-term experiment reaching histological fibrosis endpoints. Results: Cenicriviroc and pioglitazone did not affect HFD-induced fibrosis signature, indicative of no effect of these treatments on active fibrosis processes. Consistently, in the long-term treatment study, both cenicriviroc and pioglitazone did not affect HFD-induced histologically measured fibrosis. In contrast, obeticholic acid improved the early fibrogenic gene signature indicating a less fibrotic state compared with untreated HFD controls. These early gene expression changes aligned with long-term histological fibrosis endpoints and clinical data on these investigative therapeutics. Conclusions: This study highlights the potential of using short-term studies and applying a fibrogenic gene signature as an early screening tool to investigate the efficacy of investigative drugs on MASH-associated fibrosis. This signature, which is based on the active fibrosis processes in humans, may allow rapid screening of therapeutics and their combinations in translational mouse models to save time and resources.
2025-06-18 | GSE290237 | GEO
Project description:Background and aims: The incidence of metabolic dysfunction-associated steatohepatitis (MASH) and associated liver fibrosis is rapidly increasing, while pharmacological treatment options remain limited. Despite great efforts in developing novel MASH therapeutics, many investigative therapeutics that reduced fibrosis in preclinical models ultimately lacked efficacy in clinical trials. Therefore, we explored the possibility to predict the efficacy of investigative therapeutics on fibrogenic drive in the early stages of disease development and before effects on pathology become evident. Methods: Ldlr-/-.Leiden mice were fed a high-fat diet (HFD) to induce obesity and MASH. Mice were subsequently treated for four weeks with various therapeutics with established efficacy (obeticholic acid) or lack of efficacy (cenicriviroc, pioglitazone) to study their anti-fibrotic potential. Next, expression of a fibrogenic gene signature was evaluated, which predicts profibrotic processes preceding histopathologic fibrosis. The predictions were validated in parallel with a long-term experiment reaching histological fibrosis endpoints. Results: Cenicriviroc and pioglitazone did not affect HFD-induced fibrosis signature, indicative of no effect of these treatments on active fibrosis processes. Consistently, in the long-term treatment study, both cenicriviroc and pioglitazone did not affect HFD-induced histologically measured fibrosis. In contrast, obeticholic acid improved the early fibrogenic gene signature indicating a less fibrotic state compared with untreated HFD controls. These early gene expression changes aligned with long-term histological fibrosis endpoints and clinical data on these investigative therapeutics. Conclusions: This study highlights the potential of using short-term studies and applying a fibrogenic gene signature as an early screening tool to investigate the efficacy of investigative drugs on MASH-associated fibrosis. This signature, which is based on the active fibrosis processes in humans, may allow rapid screening of therapeutics and their combinations in translational mouse models to save time and resources.
2025-06-18 | GSE290235 | GEO