Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
3-O-Acetyloleanolic acid alleviates autoimmune liver injury by targeting FXR.
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Wang Yilei, Li Zhiqiang, Xiao Wei, Yongbo Xizi, Li Yiming, Li Zhifeng, Chen Daofeng, Feng Yulin
Аннотация
BACKGROUND: Autoimmune hepatitis (AIH) is a chronic, progressive inflammatory liver disease mediated by autoimmune mechanisms. 3-O-Acetyloleanolic acid (OAA), a triterpenoid isolated from the stems of syringa oblata Lindl. has demonstrated therapeutic potential for liver and immune-related disorders. The farnesoid X receptor (FXR) plays a critical role in regulating bile acid metabolism within the enterohepatic circulation and modulates metabolic dysregulation and immune homeostasis across multiple tissues.
PURPOSE: This study investigated the protective effect of OAA against concanavalin A (ConA)-induced liver injury and elucidated its underlying mechanisms.
METHODS: OAA efficacy in ConA-induced AIH mice was assessed through serum ALT/AST levels, histopathological evaluation (H&E staining), and T lymphocyte profiling. OAA's mechanism was analyzed via integrated multi-omics, with action pathways validated by Western blot (WB) and immunofluorescence. Direct targets were confirmed through cellular thermal shift assay (CETSA), surface plasmon resonance (SPR), cellular transfection, and FXR-knockdown murine models.
RESULTS: OAA significantly ameliorated ConA-induced liver injury in AIH mice. Multi-omics analysis revealed that OAA activates the primary bile acid synthesis pathway via FXR, attenuating hepatic metabolic dysregulation and injury. Critically, siRNA-mediated FXR knockdown in vitro, alongside studies in FXR-heterozygous (FXR+/-) and wild-type mice, confirmed that OAA confers hepatoprotective effects by directly binding FXR protein.
CONCLUSION: OAA demonstrates significant potential as a therapeutic candidate for mitigating liver injury in AIH, primarily through direct targeting and activation of the FXR pathway.
PURPOSE: This study investigated the protective effect of OAA against concanavalin A (ConA)-induced liver injury and elucidated its underlying mechanisms.
METHODS: OAA efficacy in ConA-induced AIH mice was assessed through serum ALT/AST levels, histopathological evaluation (H&E staining), and T lymphocyte profiling. OAA's mechanism was analyzed via integrated multi-omics, with action pathways validated by Western blot (WB) and immunofluorescence. Direct targets were confirmed through cellular thermal shift assay (CETSA), surface plasmon resonance (SPR), cellular transfection, and FXR-knockdown murine models.
RESULTS: OAA significantly ameliorated ConA-induced liver injury in AIH mice. Multi-omics analysis revealed that OAA activates the primary bile acid synthesis pathway via FXR, attenuating hepatic metabolic dysregulation and injury. Critically, siRNA-mediated FXR knockdown in vitro, alongside studies in FXR-heterozygous (FXR+/-) and wild-type mice, confirmed that OAA confers hepatoprotective effects by directly binding FXR protein.
CONCLUSION: OAA demonstrates significant potential as a therapeutic candidate for mitigating liver injury in AIH, primarily through direct targeting and activation of the FXR pathway.