Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Ergothioneine alleviates hepatic steatosis by modulating PCYT2 to restore the phosphatidylethanolamine-ACOT8 homeostasis.
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Ye Rongyi, Wang Yihan, Wang Kebo, Huang Nan, Liu Guo, Gao Dexin, Li Xinru, Yang Mengxue, Wang Jing, Chen Chen
Аннотация
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) represents a burgeoning global health burden with limited pharmacological options. Ergothioneine (EGT), a naturally occurring antioxidant, shows potential hepatoprotective effects; however, the exact mechanisms by which EGT regulates lipid metabolism in NAFLD remain elusive.
PURPOSE: This study aimed to investigate the therapeutic efficacy and potential mechanisms of EGT in high-fat diet (HFD)-induced NAFLD.
METHODS: NAFLD was induced in ApoE-/- mice via a 12-week HFD regimen, with concurrent oral administration of low- (1.7 mg/kg) or high-dose (17 mg/kg) EGT. We integrated in vivo multi-omics profiling with in vitro assays to identify the metabolic pathways modulated by EGT.
RESULTS: EGT administration robustly ameliorated HFD-induced hepatic steatosis, liver injury, and dyslipidemia. We identified a critical regulatory axis wherein EGT inhibits phosphatidylethanolamine cytidylyltransferase 2 (PCYT2) expression, thereby dampening the accumulation of pathogenic phosphatidylethanolamine (PE) species. This suppression of PE synthesis acts as a trigger to upregulate acyl-CoA thioesterase 8 (ACOT8), a key enzyme in lipid turnover. Notably, the protective effects of EGT against palmitic acid-induced lipid accumulation were blunted by the PE synthesis inhibitor meclizine, validating the PE-ACOT8 pathway as the primary target of EGT.
CONCLUSION: This study unveils a previously unrecognized mechanism by which EGT alleviates NAFLD: the restoration of the PCYT2/PE/ACOT8 signaling axis. By correcting phospholipid composition to upregulate ACOT8, EGT restores lipid homeostasis, presenting a compelling natural compound-based strategy for NAFLD intervention.
PURPOSE: This study aimed to investigate the therapeutic efficacy and potential mechanisms of EGT in high-fat diet (HFD)-induced NAFLD.
METHODS: NAFLD was induced in ApoE-/- mice via a 12-week HFD regimen, with concurrent oral administration of low- (1.7 mg/kg) or high-dose (17 mg/kg) EGT. We integrated in vivo multi-omics profiling with in vitro assays to identify the metabolic pathways modulated by EGT.
RESULTS: EGT administration robustly ameliorated HFD-induced hepatic steatosis, liver injury, and dyslipidemia. We identified a critical regulatory axis wherein EGT inhibits phosphatidylethanolamine cytidylyltransferase 2 (PCYT2) expression, thereby dampening the accumulation of pathogenic phosphatidylethanolamine (PE) species. This suppression of PE synthesis acts as a trigger to upregulate acyl-CoA thioesterase 8 (ACOT8), a key enzyme in lipid turnover. Notably, the protective effects of EGT against palmitic acid-induced lipid accumulation were blunted by the PE synthesis inhibitor meclizine, validating the PE-ACOT8 pathway as the primary target of EGT.
CONCLUSION: This study unveils a previously unrecognized mechanism by which EGT alleviates NAFLD: the restoration of the PCYT2/PE/ACOT8 signaling axis. By correcting phospholipid composition to upregulate ACOT8, EGT restores lipid homeostasis, presenting a compelling natural compound-based strategy for NAFLD intervention.