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.

中文翻译：

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抑制 HSP20 通过刺激 ERK2 依赖性自噬改善脂肪变性肝病

热休克蛋白 20 (HSP20) 成为心脏自噬的新型调节剂。尽管如此，HSP20 在肝脏中的详细功能及其对自噬的影响仍不清楚。在这里，我们观察到小鼠和患有代谢功能障碍相关脂肪肝病（MASLD）（以前称为非酒精性脂肪肝病（NAFLD））的小鼠和患者的肝组织中HSP20表达增加。肝脏特异性下调 HSP20 可减轻肥胖小鼠的肝脏脂肪变性和胰岛素抵抗，而上调 HSP20 可促进脂质沉积和肝细胞死亡。从机制上来说，液相色谱串联质谱 (LC-MS/MS) 揭示 HSP20 与磷酸化的细胞外调节蛋白激酶 2 (ERK2) 相互作用，并通过双特异性磷酸酶 6 (DUSP6) 阻止其去磷酸化，从而导致 ERK2 介导的自噬抑制。导致严重的饱和脂肪酸（SFA）引发的肝细胞死亡。重要的是，ERK 抑制剂可以改善这种不良反应。我们的数据揭示了 HSP20 如何通过增强 ERK2 磷酸化来增加 SFA 诱导的肝损伤易感性的框架，这代表了对抗 MASLD 的合理治疗干预。