GDF10 attenuates MASH progression by restoring quiescent hepatic stellate cells via competitive inhibition of TGF-β/SMAD2 signaling.

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. MASH with progressive fibrosis lacks effective therapies due to incomplete understanding of HSCs regulation. Here, we identify growth differentiation factor 10 (GDF10) as a master regulator of HSCs quiescence that ameliorates fibrosis through shifting HSC functions to restore HSC balance of transcriptional and metabolic reprogramming. Single-cell RNA sequencing revealed HSC-specific Gdf10 expression inversely correlated with fibrotic activation. In murine models of diet-induced MASH and CCl4-induced fibrosis, AAV-mediated Gdf10 overexpression reduced collagen deposition, serum ALT/AST, and fibrogenic gene expression without perturbing glucose or lipid metabolism. Mechanistically, GDF10 competitively bound TGF-β receptor 2 (TβR2), inhibiting SMAD2/3 phosphorylation and nuclear translocation, ultimately suppressing TGFβ1-driven extracellular matrix production, and reversing the activated HSCs phenotype and their hypermetabolic states. Leveraging this pathway, we developed liver-targeted lipid nanoparticles (LNPs) encapsulating mGdf10 mRNA, which selectively delivered Gdf10 to HSCs, reversed fibrosis in multiple animal models. Clinically, GDF10 expression correlated with fibrosis severity in human cirrhotic livers. Our findings establish GDF10 as a dual-function modulator of TGF-β signaling and HSC metabolism, offering a targeted therapeutic strategy for liver fibrosis.