Pantothenic acid ameliorates hepatic fibrosis by targeting IGFBP6 to regulate the TGF-β/SMADs pathway
Zhengxin Jin, Zhengsen Jin, Zeyu Liu, Yi Yin, Yuchen Zhang, Ying Zhang, Jianning Kang, Yuepeng Fang, Wei Jiang, Bin Ning
Abstract
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. Identification of IGFBP6 as a driver of liver fibrosis. Pantothenic acid promotes ubiquitin-dependent degradation by targeting IGFBP6, inhibits the TGF-β/SMADs signaling pathway, and demonstrates therapeutic efficacy in a mouse model.