Year: 2026
Type: preprint
Abstract: Background & Aims Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of chronic liver disease, and liver fibrosis is the principal determinant of disease progression and clinical outcome. We recently showed that non-apoptotic caspase-8 in hepatocytes is upregulated in MASH and leads to the induction and secretion of meteorin, which promotes hepatic stellate cell (HSC) activation and liver fibrosis. We address here the major mechanistic question arising from this study, namely how non-apoptotic caspase-8 induces pro-fibrotic meteorin in hepatocytes in MASH. Methods Mechanistic studies were performed using AML12 hepatocytes; primary mouse and human hepatocytes; and diet-induced mouse models of MASH with hepatocyte-specific caspase-8 deletion. YY1 post-translational modifications were identified by LC–MS/MS and investigated using phosphorylation-defective and phosphomimetic YY1 mutants. Genetic and biochemical approaches were used to interrogate the caspase-8 DED–SRC–GSK3β pathway, and its relevance was assessed in human MASH liver specimens. Results In vitro mechanistic stduies showed that the amino-terminal death effector domain (DED) of caspase-8 activated a SRC–GSK3β signaling cascade that promoted phosphorylation of YY1 at Ser247, resulting in YY1 nuclear localization and Metrn induction. Disruption of the conserved DED RXDLL motif impaired SRC activation, YY1 phosphorylation, and Metrn expression. Hepatocyte YY1 overexpression increased Metrn expression and fibrosis in wild-type MASH mice but not in hepatocyte-caspase-8-deficient mice. In contrast, phosphomimetic YY1-S247D restored these endpoints even when hepatocyte caspase-8 was lacking. Studies in primary mouse and human hepatocytes and human MASH liver specimens supported conservation of this signaling pathway. Conclusions These findings identify YY1 Ser247 phosphorylation as a critical molecular event linking non-apoptotic hepatocyte caspase-8 signaling to METRN induction and MASH fibrosis and define a previously unrecognized DED–SRC–GSK3β–YY1 signaling axis with potential therapeutic relevance.
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G144283012, Mini-Livers Derived from Human IPS Cells for Modeling Steatosis and Therapy, Discovery of novel therapeutic targets for NASH through deep phenotyping of human knockouts and mechanistic studies, Cancer Center Support Grant, The Columbia University Digestive and Liver Disease Research Center
OpenAlex ID: W7220663931