Luo Yuan-Yuan, Guan Ya-Ping, Zhan Hong-Fei, Sun Chun-Yan, Cai Ling-Yan, Tao Ke-Gong, Lin Yong, Zeng Xin
Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Gastroenterology, Shanghai Changzheng Hospital, Navy Military Medical University, Shanghai, China.
Front Pharmacol. 2025 Apr 3;16:1517250. doi: 10.3389/fphar.2025.1517250. eCollection 2025.
Liver cirrhosis seriously harms human health and fibrosis is the essential pathological process of cirrhosis. Recently, circular RNAs (circRNAs) were found to play critical roles in liver fibrosis, but the key circRNAs and precise mechanisms remained unclear. This study aimed to investigate the effect of circ_0098181 in fibrogenesis and explore its mechanism.
RNA sequencing was conducted to identify circRNA signatures in human liver cirrhotic tissues. Hepatic stellate cells (HSCs) (including primary rat HSCs, LX2, HSC-T6) and carbon tetrachloride (CCl) induced liver cirrhosis model were used to explore the role of circ_0098181 on HSC activation and liver fibrogenesis and . RNA sequencing, RNA pull-down, mass spectrometry, and RNA immunoprecipitation (RIP) experiments were performed to elucidate the mechanism.
Circ_0098181 was obviously reduced in human fibrotic liver tissues and activated HSCs. Exogenous administration of circ_0098181 blocked the activation, proliferation, and migration of HSCs and mitigated the progression of CCl-induced liver fibrosis . Mechanistically, adenosine deaminase acting on RNA1 (ADAR1) combined with the intronic complementary sequences (ICSs) in the flanking regions, thereby regulating the biogenesis of circ_0098181. RNA sequencing and qRT-PCR revealed the suppression of circ_0098181 on pro-inflammation cytokines expression (TNFα, Fas, Cxcl11, etc.). RNA pull-down, mass spectrometry, and RIP experiments indicated that pyruvate kinase M2 (PKM2) was the direct target of circ_0098181. Circ_0098181 bound to PKM2, restrained its nuclear translocation and phosphorylation.
In conclusion, circ_0098181 exerts a significant anti-fibrotic effect by binding PKM2 to repress its nuclear translocation and inhibiting hepatic inflammation, suggesting the promising therapeutic merit in liver cirrhosis.
肝硬化严重危害人类健康，纤维化是肝硬化的本质病理过程。最近，发现环状RNA（circRNAs）在肝纤维化中起关键作用，但关键的circRNAs及其精确机制仍不清楚。本研究旨在探讨circ_0098181在纤维化形成中的作用并探索其机制。
进行RNA测序以鉴定人肝硬化组织中的circRNA特征。使用肝星状细胞（HSCs）（包括原代大鼠HSCs、LX2、HSC-T6）和四氯化碳（CCl）诱导的肝硬化模型来探讨circ_0098181对HSC激活和肝纤维化的作用。进行RNA测序、RNA下拉、质谱分析和RNA免疫沉淀（RIP）实验以阐明其机制。
circ_0098181在人纤维化肝组织和活化的HSCs中明显减少。外源性给予circ_0098181可阻断HSCs的激活、增殖和迁移，并减轻CCl诱导的肝纤维化进展。机制上，作用于RNA1的腺苷脱氨酶（ADAR1）与侧翼区域的内含子互补序列（ICSs）结合，从而调节circ_0098181的生物合成。RNA测序和qRT-PCR显示circ_0098181对促炎细胞因子表达（TNFα、Fas、Cxcl11等）有抑制作用。RNA下拉、质谱分析和RIP实验表明丙酮酸激酶M2（PKM2）是circ_0098181的直接靶点。circ_0098181与PKM2结合，抑制其核转位和磷酸化。
总之，circ_0098181通过结合PKM2抑制其核转位并抑制肝脏炎症发挥显著的抗纤维化作用，提示其在肝硬化治疗中具有潜在的治疗价值。
