GDF10 cell-autonomously alleviates fibrotic response in HSCs

Liver fibrosis has emerged as the primary determinant of outcomes in metabolic dysfunction associated steatohepatitis (MASH). Quiescent hepatic stellate cells (HSCs) differentiate into activated HSCs or myofibroblasts, which drives liver fibrosis and contribute to the progressive loss of hepatic function. However, the underlying mechanisms of autocrine signals driving and reversing HSC activation and fibrotic response within the liver microenvironment remains incompletely delineated. Here, through searching for cytokines highly enriched expression in HSCs compared to other liver cell types by single-cell transcriptomic analysis, we found that Gdf10 is specifically expressed in HSCs, whereas its protein levels were elevated during fibrosis associated with MASH and CCl4-induced liver injury. The functional importance of GDF10 in alleviating the progression of liver fibrosis was demonstrated using gain and loss of GDF10 function mice and cultured HSCs treated with GDF10. Furthermore, the novel HSC-targeted delivery strategy of Gdf10 mRNA in fibrosis mice reversed their fibrotic phenotypes. These results reveal a new regulatory pathway in MASH microenvironment, suggesting a promising strategy for delivering drugs that can shift HSC functions to restore HSC balance.