Jin Zhengxin, Jin Zhengsen, Liu Zeyu, Yin Yongcheng, Zhang Yuchen, Zhang Ying, Kang Jianning, Fang Yuepeng, Jiang Wei, Ning Bin
Jinan Central Hospital, Shandong University, No.105, Jiefang Road, Jinan, Shandong, China.
Department of Clinical Pharmacology of Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China.
Commun Biol. 2025 Jul 29;8(1):1127. doi: 10.1038/s42003-025-08527-5.
Hepatic fibrosis progression involves complex multicellular crosstalk, highlighting the critical need to identify key therapeutic targets. In this study, we identify insulin-like growth factor binding protein 6 (IGFBP6) as a marker specifically enriched in hepatic stellate cells (HSCs) and upregulated in viral hepatitis-associated fibrosis. Using thioacetamide (TAA)-induced mouse models and transforming growth factor-β (TGF-β)-stimulated cell models, we demonstrate the pro-fibrotic role of IGFBP6. Through network pharmacology screening, pantothenic acid (PA) is identified as a potent compound targeting IGFBP6. PA administration significantly reduces collagen deposition, attenuates HSCs' activation, and decreases hepatic fibrosis-related markers. Notably, PA maintains efficacy in mouse models with established fibrosis. Mechanistically, PA directly interacts with IGFBP6, inducing ubiquitin-dependent degradation and inhibiting TGF-β/SMADs signaling. This study identifies IGFBP6 as a driver of hepatic fibrosis and validates PA as a potent therapeutic agent. Therefore, targeting IGFBP6 with PA offers a potential clinical treatment strategy for hepatic fibrosis.
肝纤维化进展涉及复杂的多细胞相互作用，这凸显了识别关键治疗靶点的迫切需求。在本研究中，我们确定胰岛素样生长因子结合蛋白6（IGFBP6）是一种在肝星状细胞（HSC）中特异性富集且在病毒性肝炎相关纤维化中上调的标志物。使用硫代乙酰胺（TAA）诱导的小鼠模型和转化生长因子-β（TGF-β）刺激的细胞模型，我们证明了IGFBP6的促纤维化作用。通过网络药理学筛选，确定泛酸（PA）是一种靶向IGFBP6的有效化合物。给予PA可显著减少胶原蛋白沉积，减弱肝星状细胞的激活，并降低肝纤维化相关标志物。值得注意的是，PA在已形成纤维化的小鼠模型中仍保持疗效。从机制上讲，PA直接与IGFBP6相互作用，诱导泛素依赖性降解并抑制TGF-β/SMAD信号通路。本研究确定IGFBP6是肝纤维化的驱动因素，并验证了PA作为一种有效的治疗药物。因此，用PA靶向IGFBP6为肝纤维化提供了一种潜在的临床治疗策略。
