Heat shock protein 20 (HSP20) emerges as a novel regulator of autophagy in the heart. Nonetheless, the detailed function of HSP20 in 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 (NAFLD). 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 (LC-MS/MS) revealed that HSP20 interacts with phosphorylated extracellular regulated protein kinases 2 (ERK2) and prevents its dephosphorylation by dual specificity phosphatase 6 (DUSP6), leading to ERK2-mediated repression of autophagy, resulting in aggravated saturated fatty acid (SFA)-triggered hepatocyte death. Importantly, such adverse effects could be ameliorated by ERK inhibitor. Our data reveals 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.

This article contains supplementary material online at https://doi.org/10.2337/figshare.25360012.

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