Ergothioneine alleviates hepatic steatosis by modulating PCYT2 to restore the phosphatidylethanolamine-ACOT8 homeostasis

  • Phytomedicine. 2026 Aug:158:158238. doi: 10.1016/j.phymed.2026.158238.
Rongyi Ye  1 ,  Yihan Wang  1 ,  Kebo Wang  2 ,  Nan Huang  1 ,  Guo Liu  1 ,  Dexin Gao  1 ,  Xinru Li  1 ,  Mengxue Yang  1 ,  Jing Wang  3 ,  Chen Chen  4
Affiliations
  • 1. School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
  • 2. Shandong Center for Food Safety Risk Assessment, Shandong Center for Disease Control and Prevention, Jinan 250014, China.
  • 3. Institute of Quality Standard and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing 100081, China; State Key Laboratory for Quality and Safety of Agro-Products; Institute of Plant Virology, Ningbo University, Ningbo 315211, China. Electronic address: [email protected].
  • 4. School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China; State Key Laboratory for Quality and Safety of Agro-Products; Institute of Plant Virology, Ningbo University, Ningbo 315211, China. Electronic address: [email protected].
PMID: 42275877 DOI: 10.1016/j.phymed.2026.158238
Abstract

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.

Keywords
Acyl-coA thioesterase 8; Ergothioneine; Lipid metabolism; Non-alcoholic fatty liver disease; Phosphatidylethanolamine.
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