Endothelial c-Maf prevents MASLD-like liver fibrosis by regulating chromatin accessibility to suppress pathogenic microvascular cell subsets
Abstract
Background and Aims Liver sinusoidal endothelial cells (LSEC) are highly specialized within the hepatic vascular niche, controlling liver function and disease pathogenesis by angiocrine signaling. Recently, we identified GATA4 as a major transcription factor controlling LSEC development and protecting against liver fibrosis. As the transcription factor c-Maf was strongly downregulated in Gata4 -deficient LSEC, we hypothesized that c-Maf might be an important downstream effector of GATA4 in LSEC differentiation and liver fibrogenesis. Methods Clec4g-iCre/Maf fl/fl ( Maf LSEC-KO ) mice with LSEC-specific Maf deficiency were generated and liver tissue was analyzed histologically. LSEC were isolated for bulk RNA-seq, ATAC-seq, and single-cell (sc) RNA-seq analysis. Maf LSEC-KO livers were analyzed after MASH diet. The expression of MAF and its targets was analyzed in published human scRNA-seq data. Results Endothelial Maf deficiency resulted in perisinusoidal liver fibrosis (Sirius Red 0.46% vs . 2.92%; p <0.05) without affecting metabolic liver zonation, accompanied by a switch from sinusoidal to continuous endothelial cell identity, which was aggravated upon feeding a MASH diet ( p <0.01). Furthermore, endothelial Maf deficiency caused LSEC proliferation ( p <0.05) and expression of profibrotic angiocrine factors such as Pdgfb , Igfbp5 , Flrt2, and Cxcl12 , of which FLRT2 ( p <0.01) and CXCL12 ( p <0.001) activated hepatic stellate cells in vitro . scRNA-seq revealed replacement of zonated LSEC subpopulations by capillarized, proliferative, sprouting and secretory endothelial cell subsets promoting liver fibrogenesis and angiogenesis. This fundamental dysregulation of LSEC gene expression and differentiation was caused by changes in chromatin accessibility and transcription factor activity following loss of Maf . Notably, endothelial MAF expression was also significantly reduced in human liver cirrhosis patients ( p <0.0001). Conclusions Hepatic endothelial c-Maf protects against metabolic dysfunction-associated steatohepatitis-like liver fibrosis and regulates endothelial differentiation and zonation by controlling chromatin opening. Impact and Implications This work builds on the known importance of liver sinusoidal endothelial cells (LSEC) in liver function and disease. Here, transcription factor c-Maf is identified as a master regulator in maintaining normal LSEC differentiation and zonation, thereby protecting against development of liver fibrosis/cirrhosis. The findings are significant for researchers and clinicians focusing on liver disease, as they suggest potential new targets for therapeutic intervention. These findings could instruct the development of novel preventive treatment options and antifibrotic therapy regimens as well as liver repair strategies, benefiting patients, clinicians and policy makers in the management of liver disease.
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BibTeX
@article{winkler2026endothelial,
title = {{Endothelial c-Maf prevents MASLD-like liver fibrosis by regulating chromatin accessibility to suppress pathogenic microvascular cell subsets}},
author = {Manuel Winkler and Theresa Staniczek and Maximilian Suhayda and Sina Wietje Kürschner-Zacharias and Johannes Hoffmann and Julio Cordero and Linda Kraske and Hannah Maude and Dorka Nagy and Rita Manco and Carsten Sticht and Michelle Neßling and Karsten Richter and Gergana Dobreva and Anna Maria Randi and Inês Cebola and Kai Schledzewski and Philipp-Sebastian Reiners-Koch and Sergij Goerdt and Christian David Schmid},
journal = {JHEP Reports Innovation in Hepatology},
year = {2026},
month = sep,
doi = {10.1016/j.jhepr.2025.101475},
url = {https://hal.science/hal-05749473v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Endothelial c-Maf prevents MASLD-like liver fibrosis by regulating chromatin accessibility to suppress pathogenic microvascular cell subsets
AU - Manuel Winkler
AU - Theresa Staniczek
AU - Maximilian Suhayda
AU - Sina Wietje Kürschner-Zacharias
AU - Johannes Hoffmann
AU - Julio Cordero
AU - Linda Kraske
AU - Hannah Maude
AU - Dorka Nagy
AU - Rita Manco
AU - Carsten Sticht
AU - Michelle Neßling
AU - Karsten Richter
AU - Gergana Dobreva
AU - Anna Maria Randi
AU - Inês Cebola
AU - Kai Schledzewski
AU - Philipp-Sebastian Reiners-Koch
AU - Sergij Goerdt
AU - Christian David Schmid
PY - 2026
DA - 2026/09/14
JO - JHEP Reports Innovation in Hepatology
DO - 10.1016/j.jhepr.2025.101475
UR - https://hal.science/hal-05749473v1
AB - Background and Aims Liver sinusoidal endothelial cells (LSEC) are highly specialized within the hepatic vascular niche, controlling liver function and disease pathogenesis by angiocrine signaling. Recently, we identified GATA4 as a major transcription factor controlling LSEC development and protecting against liver fibrosis. As the transcription factor c-Maf was strongly downregulated in Gata4 -deficient LSEC, we hypothesized that c-Maf might be an important downstream effector of GATA4 in LSEC differentiation and liver fibrogenesis. Methods Clec4g-iCre/Maf fl/fl ( Maf LSEC-KO ) mice with LSEC-specific Maf deficiency were generated and liver tissue was analyzed histologically. LSEC were isolated for bulk RNA-seq, ATAC-seq, and single-cell (sc) RNA-seq analysis. Maf LSEC-KO livers were analyzed after MASH diet. The expression of MAF and its targets was analyzed in published human scRNA-seq data. Results Endothelial Maf deficiency resulted in perisinusoidal liver fibrosis (Sirius Red 0.46% vs . 2.92%; p <0.05) without affecting metabolic liver zonation, accompanied by a switch from sinusoidal to continuous endothelial cell identity, which was aggravated upon feeding a MASH diet ( p <0.01). Furthermore, endothelial Maf deficiency caused LSEC proliferation ( p <0.05) and expression of profibrotic angiocrine factors such as Pdgfb , Igfbp5 , Flrt2, and Cxcl12 , of which FLRT2 ( p <0.01) and CXCL12 ( p <0.001) activated hepatic stellate cells in vitro . scRNA-seq revealed replacement of zonated LSEC subpopulations by capillarized, proliferative, sprouting and secretory endothelial cell subsets promoting liver fibrogenesis and angiogenesis. This fundamental dysregulation of LSEC gene expression and differentiation was caused by changes in chromatin accessibility and transcription factor activity following loss of Maf . Notably, endothelial MAF expression was also significantly reduced in human liver cirrhosis patients ( p <0.0001). Conclusions Hepatic endothelial c-Maf protects against metabolic dysfunction-associated steatohepatitis-like liver fibrosis and regulates endothelial differentiation and zonation by controlling chromatin opening. Impact and Implications This work builds on the known importance of liver sinusoidal endothelial cells (LSEC) in liver function and disease. Here, transcription factor c-Maf is identified as a master regulator in maintaining normal LSEC differentiation and zonation, thereby protecting against development of liver fibrosis/cirrhosis. The findings are significant for researchers and clinicians focusing on liver disease, as they suggest potential new targets for therapeutic intervention. These findings could instruct the development of novel preventive treatment options and antifibrotic therapy regimens as well as liver repair strategies, benefiting patients, clinicians and policy makers in the management of liver disease.
SN - 2589-5559
ER -