Inhibition of HSP20 Ameliorates Steatotic Liver Disease by Stimulating ERK2-Dependent Autophagy

HSP20 emerges as a novel regulator of autophagy in the heart. Nonetheless, the detailed function of HSP20 in the liver and its effect on autophagy remain unknown. Here, we observed that HSP20 expression is increased in liver tissues from mice and patients with metabolic dysfunction–associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease. Liver-specific downregulation of HSP20 mitigates hepatic steatosis and insulin resistance in obese mice, while upregulating HSP20 promotes lipid deposition and hepatocyte cell death. Mechanistically, liquid chromatography–tandem mass spectrometry revealed that HSP20 interacts with phosphorylated extracellular regulated protein kinase 2 (ERK2) and prevents its dephosphorylation by dual specificity phosphatase 6, leading to ERK2-mediated repression of autophagy and resulting in aggravated saturated fatty acid (SFA)–triggered hepatocyte death. Importantly, such adverse effects could be ameliorated by ERK inhibitor. Our data reveal a framework of how HSP20 increases susceptibility of SFA-induced liver injury through enhancing ERK2 phosphorylation, which represents a plausible therapeutic intervention to combat MASLD.

• HSP20 expression was increased in the livers of mice and people living with metabolic dysfunction–associated steatotic liver disease and positively correlated with steatosis grade and body mass.

• Upregulating HSP20 sensitizes hepatocytes to lipotoxicity by inhibiting autophagy.

• HSP20 interacts with phosphorylated extracellular regulated protein kinase 2 and prevents its dephosphorylation by phosphatase dual specificity phosphatase 6, leading to aggravation of saturated fatty acid–triggered hepatocyte death by suppressing autophagy function.

• The HSP20-extracellular regulated protein kinase 2 pathway is an important target to maintain liver homeostasis in patients with metabolic disorders.