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

Nov 24, 2025International journal of biological sciences

GDF10 may slow fatty liver disease by keeping liver scar cells inactive through blocking TGF-beta/SMAD2 signals

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Abstract

GDF10 is identified as a master regulator of quiescent hepatic stellate cells, which may ameliorate liver fibrosis.

Quiescent hepatic stellate cells differentiate into activated cells, contributing to liver fibrosis and loss of function.
In murine models of metabolic dysfunction-associated steatohepatitis and fibrosis, GDF10 overexpression reduced collagen deposition and fibrogenic gene expression.
GDF10 inhibits TGF-β receptor signaling, which is associated with reduced extracellular matrix production and reversal of activated cell phenotype.
Liver-targeted lipid nanoparticles delivering GDF10 mRNA reversed fibrosis in multiple animal models.
In human cirrhotic livers, GDF10 expression is correlated with the severity of fibrosis.

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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-specificexpression inversely correlated with fibrotic activation. In murine models of diet-induced MASH and CCl4-induced fibrosis, AAV-mediatedoverexpression 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) encapsulatingmRNA, which selectively deliveredto HSCs, reversed fibrosis in multiple animal models. Clinically,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. Gdf10Gdf10mGdf10Gdf10GDF10

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

Abstract

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