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  3. Ethanol-Induced Hepatic Ferroptosis Is Mediated by PERK-Dependent MAMs Formation: Preventive Role of Quercetin

Ethanol-Induced Hepatic Ferroptosis Is Mediated by PERK-Dependent MAMs Formation: Preventive Role of Quercetin

  • Mol Nutr Food Res. 2024 Mar 19:e2300343. doi: 10.1002/mnfr.202300343.
Hongkun Lin 1 2,  Xiaoping Guo 1,  Jingjing Liu 3,  Yuhan Tang 1,  Li Chen 1,  Huimin Chen 1,  Ying Zhao 1,  Lili Wang 1,  Hongxia Li 1,  Jiasheng Yu 4,  Ping Yao 1 5 6
Affiliations

Affiliations

  • 1 Department of Nutrition and Food Hygiene, School of Public Health，Tongji Medical College, Huazhong University of Science & Technology, 13 Hangkong Road, Wuhan, 430030, P. R. China.
  • 2 Department of Nutrition, School of Public Health, Wuhan University, Wuhan, 430071, P. R. China.
  • 3 Henan Provincial Center for Disease Control and Prevention, Zhengzhou, 450016, P. R. China.
  • 4 Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China.
  • 5 Ministry of Education Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, 13 Hangkong Road, Wuhan, 430030, P. R. China.
  • 6 Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, 13 Hangkong Road, Wuhan, 430030, P. R. China.
PMID: 38501770 DOI: 10.1002/mnfr.202300343
Abstract

Scope: Iron deposition is frequently observed in alcoholic liver disease (ALD), which indicates a potential role of Ferroptosis in its development. This study aims to explore the effects of quercetin on Ferroptosis in ALD and elucidates the underlying mechanism involving the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs) mediated by protein kinase RNA-like endoplasmic reticulum kinase (PERK).

Methods and results: C57BL/6J mice are fed either a regular or an ethanol-containing liquid diet (with 28% energy form ethanol) with or without quercetin supplementation (100 mg kg-1 BW) for 12 weeks. Ethanol feeding or treatment induced Ferroptosis in mice and AML12 cells, which is associated with increased MAMs formation and PERK expression within MAMs. Quercetin attenuates these changes and protects against ethanol-induced liver injury. The antiferroptotic effect of quercetin is abolished by Ferroptosis inducers, but mimicked by Ferroptosis inhibitors and PERK knockdown. The study demonstrates that PERK structure, rather than its kinase activity (transfected with the K618A site mutation that inhibits kinase activity-ΔK plasmid or protein C terminal knockout-ΔC plasmid of PERK), mediates the enhanced MAMs formation and Ferroptosis during the ethanol exposure.

Conclusion: Quercetin ameliorates ethanol-induced liver injury by inhibiting Ferroptosis via modulating PERK-dependent MAMs formation.

Keywords

ALD; MAMs; PERK; ferroptosis; quercetin.

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