Yin Zhaoqing, Yue Caibin, Li Zhipeng, Guo Xiuwen, Wang Guohao, Zhang Hao, Wang Wei, Liu Lan
Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan, China.
Shandong Province Engineering Research Center for Multidisciplinary Research on Hepatobiliary and Pancreatic Malignant Tumors, Jinan, China.
Cell Mol Life Sci. 2025 Sep 8;82(1):338. doi: 10.1007/s00018-025-05847-x.
Metabolic associated steatohepatitis (MASH) is a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD) characterized by hepatocellular injury, inflammation, and fibrosis. Despite advances in understanding its pathophysiology, the molecular mechanisms driving MASH progression remain unclear. This study investigates the role of long non-coding RNA Linc01271 in MASLD/MASH pathogenesis, ant its involvement in the miR-149-3p/RAB35 axis and PI3K/AKT/mTOR signaling pathway. Transcriptome sequencing and RT-qPCR revealed significant upregulation of Linc01271 in MASH tissues, which correlated with lipid accumulation and inflammatory responses. Knockdown of Linc01271 in THLE-2 cells reduced lipid droplet formation, triglyceride and cholesterol levels, and the expression of lipid metabolism-related genes (CD36, ACC1, FASN) and pro-inflammatory cytokines (IL-6, IL-8, TGF-β1). Conversely, Linc01271 overexpression had the opposite effect. Dual-luciferase reporter assays confirmed Linc01271's interaction with miR-149-3p, which regulates RAB35, a downstream target of miR-149-3p. Knockdown of Linc01271 in mice attenuated MASH progression, reducing body weight, liver weight, blood glucose levels, and liver injury markers. These findings demonstrate that Linc01271 promotes lipid synthesis and inflammatory responses through the miR-149-3p/RAB35 axis and PI3K/AKT/mTOR pathway, highlighting its potential as a therapeutic target for MASLD/MASH. Further research is warranted to develop therapeutic agents targeting Linc01271 for clinical applications.
代谢相关脂肪性肝炎（MASH）是代谢功能障碍相关脂肪性肝病（MASLD）的一种严重形式，其特征为肝细胞损伤、炎症和纤维化。尽管在理解其病理生理学方面取得了进展，但驱动MASH进展的分子机制仍不清楚。本研究调查了长链非编码RNA Linc01271在MASLD/MASH发病机制中的作用，及其在miR-149-3p/RAB35轴和PI3K/AKT/mTOR信号通路中的参与情况。转录组测序和RT-qPCR显示，MASH组织中Linc01271显著上调，这与脂质积累和炎症反应相关。在THLE-2细胞中敲低Linc01271可减少脂滴形成、甘油三酯和胆固醇水平，以及脂质代谢相关基因（CD36、ACC1、FASN）和促炎细胞因子（IL-6、IL-8、TGF-β1）的表达。相反，Linc01271过表达则产生相反的效果。双荧光素酶报告基因检测证实Linc01271与miR-149-3p相互作用，miR-149-3p可调节miR-149-3p的下游靶点RAB35。在小鼠中敲低Linc01271可减轻MASH进展，降低体重、肝脏重量、血糖水平和肝损伤标志物。这些发现表明，Linc01271通过miR-149-3p/RAB35轴和PI3K/AKT/mTOR途径促进脂质合成和炎症反应，突出了其作为MASLD/MASH治疗靶点的潜力。有必要进一步开展研究，开发针对Linc01271的治疗药物用于临床应用。
