Senkyunolide I targets CXCR4 to attenuate liver fibrosis via suppression of the NLRP3/GSDMD pathway.

Liver fibrosis is a progressive pathological disorder characterized by excessive extracellular matrix (ECM) deposition, resulting in hepatic architectural distortion and functional impairment. Despite its clinical importance, effective therapeutic options remain limited. This study evaluated the antifibrotic potential of senkyunolide I (SI), a bioactive phthalide compound derived from Ligusticum chuanxiong Hort., in both in vivo and in vitro models. In a CCl4-induced mouse model of liver fibrosis, SI treatment significantly attenuated fibrosis progression, as indicated by a reduced liver index, decreased serum ALT and AST levels, diminished histopathological damage, suppressed collagen deposition, and ameliorated hepatocyte ultrastructural injury. Additionally, SI inhibited hepatic inflammation by modulating the CXCR4/NLRP3/GSDMD pathway. In vitro experiments demonstrated that SI effectively mitigated LPS + nigericin (Nig)-induced pyroptosis in AML-12 cells and reduced collagen deposition in primary hepatic stellate cells (HSCs) exposed to conditioned medium from injured hepatocytes. Mechanistic studies revealed that SI directly binds to CXCR4, suppressing its expression and subsequently inactivating the NLRP3/GSDMD signalling cascade. These findings suggest that SI exerts its antifibrotic effects via CXCR4 pathway inhibition, positioning it as a promising therapeutic candidate for liver fibrosis treatment.