Liver fibrosis is a serious threat to human life and health. Activated hepatic stellate cells (HSCs) play a key role in the occurrence and development of liver fibrosis. Studies have reported that microRNAs (miRNAs/miRs) are involved in the pathological process of fibrosis, as well as its relevance in clinical diagnosis. However, the role of miR221 in hepatic fibrosis remains controversial. Remarkably, transforming growth factor‑β (TGF‑β1) caused HSC dysfunction in autophagic activation, characterized by an increase in P62 aggregation and LC3II expression. The present study aimed to determine whether autophagy regulates hepatic fibrosis by mediating HSC activation and explore the potential targets leading to the sequence of events associated with miR221. The expression of miR221 was quantified in a liver fibrosis model in vivo and in vitro, and its specific target gene lysosome‑associated membrane glycoprotein 2 (LAMP2) was predicted by bioinformatics. The results showed that the expression levels of collagen‑I (COL‑I) and α‑smooth muscle actin (α‑SMA) were increased in miR221‑overexpressing LX2 cells, while the autophagy inducer rapamycin reversed the inhibition of autophagic flux induced by miR221. Additionally, the overexpression of LAMP2 could significantly inhibit TGF‑β1‑induced COL‑I and α‑SMA expression, which was similar to the effect of the miR221 inhibitor on the regulation of TGF‑β1‑induced HSC activation. These results indicated that miR221 may regulate TGF‑β1‑induced HSC activation through inhibiting autolysosome function by directly targeting LAMP2. The molecular mechanism of miR221 in regulating TGF‑β1‑induced HSC activation may provide novel insight into therapies to ameliorate the pathological progression of liver fibrosis.

中文翻译：

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miR221 通过直接靶向 LAMP2 抑制自噬来调节 TGF-β1 诱导的 HSC 活化。

肝纤维化是对人类生命和健康的严重威胁。活化的肝星状细胞（HSCs）在肝纤维化的发生发展中起关键作用。研究报道，microRNAs (miRNAs/miRs) 参与了纤维化的病理过程，以及其在临床诊断中的相关性。然而，miR221在肝纤维化中的作用仍存在争议。值得注意的是，转化生长因子-β (TGF-β1) 在自噬激活中引起 HSC 功能障碍，其特征是 P62 聚集和 LC3II 表达增加。本研究旨在确定自噬是否通过介导 HSC 活化来调节肝纤维化，并探索导致与 miR221 相关的事件序列的潜在靶点。在肝纤维化模型中定量 miR221 的表达体内和体外，并通过生物信息学预测其特异性靶基因溶酶体相关膜糖蛋白2（LAMP2）。结果表明，在过表达 miR221 的 LX2 细胞中，胶原蛋白-I (COL-I) 和α-平滑肌肌动蛋白 (α-SMA) 的表达水平增加，而自噬诱导剂雷帕霉素逆转了 miR221 诱导的自噬通量的抑制作用。 . 此外，LAMP2的过表达可显着抑制TGF-β1诱导的COL-I和α-SMA表达，这与miR221抑制剂对TGF-β1诱导的HSC活化的调节作用相似。这些结果表明，miR221可能通过直接靶向LAMP2抑制自溶酶体功能来调节TGF-β1诱导的HSC活化。