Academic Journal
Ergothioneine alleviates hepatic steatosis by modulating PCYT2 to restore the phosphatidylethanolamine-ACOT8 homeostasis.
| Title: | Ergothioneine alleviates hepatic steatosis by modulating PCYT2 to restore the phosphatidylethanolamine-ACOT8 homeostasis. |
|---|---|
| Authors: | Ye R; School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China., Wang Y; School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China., Wang K; Shandong Center for Food Safety Risk Assessment, Shandong Center for Disease Control and Prevention, Jinan 250014, China., Huang N; School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China., Liu G; School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China., Gao D; School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China., Li X; School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China., Yang M; School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China., Wang J; 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: w_jing2001@126.com., Chen C; 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: chenc@sdu.edu.cn. |
| Source: | Phytomedicine : international journal of phytotherapy and phytopharmacology [Phytomedicine] 2026 Aug; Vol. 158, pp. 158238. Date of Electronic Publication: 2026 Apr 25. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Urban & Fischer Verlag Country of Publication: Germany NLM ID: 9438794 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1618-095X (Electronic) Linking ISSN: 09447113 NLM ISO Abbreviation: Phytomedicine Subsets: MEDLINE |
| Imprint Name(s): | Publication: Stuttgart : Urban & Fischer Verlag Original Publication: Stuttgart ; New York : G. Fischer, c1994- |
| MeSH Terms: | Ergothioneine*/pharmacology , Non-alcoholic Fatty Liver Disease*/drug therapy , Non-alcoholic Fatty Liver Disease*/metabolism , Phosphatidylethanolamines*/metabolism, Homeostasis/drug effects ; Diet, High-Fat/adverse effects ; Lipid Metabolism/drug effects ; Liver/drug effects ; Liver/metabolism ; Antioxidants/pharmacology ; Animals ; Mice ; Male ; Mice, Inbred C57BL ; RNA Nucleotidyltransferases |
| 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. (Copyright © 2026 Elsevier GmbH. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare no competing interests. All authors have approved the final manuscript and agree to its submission to this journal. This manuscript has not been published previously and is not under consideration elsewhere. |
| Contributed Indexing: | Keywords: Acyl-coA thioesterase 8; Ergothioneine; Lipid metabolism; Non-alcoholic fatty liver disease; Phosphatidylethanolamine |
| Substance Nomenclature: | BDZ3DQM98W (Ergothioneine) 0 (Phosphatidylethanolamines) 39382-08-6 (phosphatidylethanolamine) EC 2.7.7.14 (Ethanolamine-phosphate cytidylyltransferase) 0 (Antioxidants) EC 2.7.7.- (RNA Nucleotidyltransferases) |
| Entry Date(s): | Date Created: 20260611 Date Completed: 20260620 Latest Revision: 20260620 |
| Update Code: | 20260620 |
| DOI: | 10.1016/j.phymed.2026.158238 |
| PMID: | 42275877 |
| Database: | MEDLINE |
| ISSN: | 1618-095X |
|---|---|
| DOI: | 10.1016/j.phymed.2026.158238 |