Introduction and Objective: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by chronic immune activation and stromal remodeling; however, the paracrine mechanisms linking parenchymal metabolic stress to immune-stromal responses remain poorly understood. This study aimed to identify key paracrine signals driving inflammatory and fibrogenic remodeling in MASH and to define their downstream mechanisms.Methods: Integrative transcriptomic and secretome analyses were conducted in human and murine MASH. Cell type-specific genetic approaches manipulated hepatocytes and hepatic stellate cells in vivo. Single-nucleus RNA sequencing defined immune and stromal remodeling. Paracrine signaling was assessed in vitro using primary hepatocytes, macrophages, and hepatic stellate cells. Therapeutic targeting was evaluated using hepatocyte-directed N-acetylgalactosamine-conjugated small interfering RNA.Results: Thrombospondin-2 (THBS2) was identified as a conserved secreted factor upregulated in MASH and associated with hepatic inflammation and fibrosis. Despite higher Thbs2 transcript levels in non-parenchymal cells, hepatocytes represented the dominant source of THBS2 protein under metabolic stress. Hepatocyte-specific Thbs2 overexpression exacerbated liver injury, macrophage activation, and fibrotic remodeling, whereas deletion attenuated disease progression. Single-nucleus transcriptomics revealed reduced disease-associated macrophage programs and a shift of hepatic stellate cells toward a quiescent state following loss of hepatocyte-derived THBS2. Mechanistically, THBS2 activated macrophages and hepatic stellate cells via integrin alpha 5 signaling. Hepatocyte-targeted Thbs2 silencing prevented disease progression and promoted regression of established pathology.Conclusion: Hepatocyte-derived THBS2 links metabolic stress to immune activation and fibrogenic remodeling in MASH via integrin alpha 5 signaling and represents a potential therapeutic target for metabolic liver disease.
J. Li: None. D. Hu: None. S. Fang: None. Q. Wang: None.
National Natural Science Foundation of China(82270919)
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