Zhang Chunyan, Zhao Yabin, Yan Haoyu, Guo Jianlin, Yu GuoYing
State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China.
Cell Death Discov. 2025 Sep 1;11(1):419. doi: 10.1038/s41420-025-02694-4.
Liver fibrosis represents an important pathological stage during chronic hepatopathy development, posing a significant threat to human health. Hepatic stellate cells (HSCs), an essential hepatic non-parenchymal cells, have a key effect on fibrogenesis, with their activation being a hallmark of liver fibrosis. MicroRNAs (miRNAs), the small non-coding RNAs, become the critical biomarkers and regulatory molecules in fibrotic processes. Among them, miR-125a-5p is implicated in cancer and inflammatory pathways, yet its functional role and mechanistic involvement in HSC activation remain poorly understood. According to our findings, miR-125a-5p expression was significantly decreased in TGF-β-activated HSC-T6 cells. Notably, ectopic miR-125a-5p overexpression effectively inhibited TGF-β-mediated HSC-T6 activation. Further mechanistic investigations revealed that miR-125a-5p attenuated HSC activation while ameliorating liver fibrosis through regulating the TGF-β/Smad2/3 pathway and autophagy. Additionally, TGFβR1 was miR-125a-5p's target gene. Collectively, miR-125a-5p negatively regulates HSC activation in liver fibrosis, exerting its anti-fibrotic activities through suppressing the TGF-β/Smad2/3 pathway and autophagy modulation.
肝纤维化是慢性肝病发展过程中的一个重要病理阶段，对人类健康构成重大威胁。肝星状细胞（HSCs）是肝脏重要的非实质细胞，在肝纤维化形成中起关键作用，其激活是肝纤维化的一个标志。微小RNA（miRNAs）作为小的非编码RNA，成为纤维化过程中的关键生物标志物和调节分子。其中，miR-125a-5p与癌症和炎症途径有关，但其在肝星状细胞激活中的功能作用和机制仍知之甚少。根据我们的研究结果，在转化生长因子-β（TGF-β）激活的HSC-T6细胞中，miR-125a-5p表达显著降低。值得注意的是，异位过表达miR-125a-5p可有效抑制TGF-β介导的HSC-T6激活。进一步的机制研究表明，miR-125a-5p通过调节TGF-β/Smad2/3信号通路和自噬减轻肝星状细胞激活，改善肝纤维化。此外，TGFβR1是miR-125a-5p的靶基因。总之，miR-125a-5p在肝纤维化中负向调节肝星状细胞激活，通过抑制TGF-β/Smad2/3信号通路和调节自噬发挥抗纤维化作用。
