Hyperoside attenuates NASH-associated liver fibrosis by modulating Flot2/TLR4 signaling and pyroptosis

作者：Peng Huang, Yunling Zhu, Zhiling Li, Kaixuan Zeng, Lang Qin, Jianguo Hu, Tingying Zhang, Li Zhang, Taoli Liu, Jian Qin · 发表于：International Immunopharmacology · 年份：2025 · DOI：10.1016/j.intimp.2025.116007 · 被引用次数：5 · 研究领域：Liver physiology and pathology、Liver Disease Diagnosis and Treatment、Inflammasome and immune disorders

Objectives This study aims to evaluate the therapeutic potential of hyperoside (Hyp), a flavonoid derived from Hypericum perforatum, in attenuating NASH-related liver fibrosis and to elucidate its underlying mechanism. METHODS: A NASH fibrosis model was established in C57BL/6 mice using a high-fat diet combined with (carbon tetrachloride) CCl₄. Hyp was orally administered for 8 weeks after model induction. Hepatic metabolomics, 16S rRNA sequencing, transcriptomics, and network pharmacology were integrated to identify key targets and pathways. In vitro, Lipopolysaccharides (LPS) induced pyroptosis in LX2 cells was employed to investigate the Flot2/TLR4/NLRP3 signaling axis, with siRNA-mediated Flot2 knockdown used for mechanistic validation. RESULTS: Hyp significantly reduced liver fibrosis in NASH mice. It suppressed liver metabolites (leukotriene B4 and octadecanoic acid) and reshaped gut microbiota by decreasing LPS-producing bacteria. Transcriptomic and pharmacological studies revealed suppression of NLRP3 inflammasome-driven pyroptosis signaling. Through target engagement studies encompassing molecular docking, molecular dynamics simulation, and cellular thermal shift assay (CETSA), Flot2 was confirmed as a direct binding partner of Hyp. Furthermore, Hyp effectively suppressed Flot2/TLR4-driven pyroptosis in hepatic stellate cells, with Flot2 silencing mimicking its therapeutic anti-fibrotic action. CONCLUSION: Hyperoside mitigates NASH-driven hepatic fibrosis by specific...