Abstract：
METHODS: 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).
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.
CONCLUSIONS: Quercetin ameliorates ethanol-induced liver injury by inhibiting ferroptosis via modulating PERK-dependent MAMs formation.
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.
CONCLUSIONS: Quercetin ameliorates ethanol-induced liver injury by inhibiting ferroptosis via modulating PERK-dependent MAMs formation.
摘要：
方法：在酒精性肝病（ALD）中经常观察到铁沉积，这表明铁性凋亡在其发育中的潜在作用。本研究旨在探讨槲皮素对ALD中铁凋亡的影响，并阐明蛋白激酶RNA样内质网激酶（PERK）介导的线粒体相关内质网膜（MAMs）形成的潜在机制。
结果：给C57BL/6J小鼠喂食常规或含乙醇的液体饮食（含28％能量形式的乙醇），并补充或不补充槲皮素（100mgkg-1BW）12周。乙醇喂养或治疗诱导小鼠和AML12细胞的铁凋亡，这与MAMs形成和MAMs内PERK表达增加有关。槲皮素减弱这些变化并保护免受乙醇诱导的肝损伤。槲皮素的抗铁作用被铁凋亡诱导剂消除，但被铁凋亡抑制剂和PERK敲除所模仿。研究表明，PERK结构，而不是其激酶活性（用抑制激酶活性的K618A位点突变-ΔK质粒或PERK的蛋白C末端敲除-ΔC质粒转染），在乙醇暴露期间介导增强的MAMs形成和铁凋亡。
结论：槲皮素通过调节PERK依赖性MAMs的形成，抑制铁凋亡，从而改善乙醇诱导的肝损伤。
结果：给C57BL/6J小鼠喂食常规或含乙醇的液体饮食（含28％能量形式的乙醇），并补充或不补充槲皮素（100mgkg-1BW）12周。乙醇喂养或治疗诱导小鼠和AML12细胞的铁凋亡，这与MAMs形成和MAMs内PERK表达增加有关。槲皮素减弱这些变化并保护免受乙醇诱导的肝损伤。槲皮素的抗铁作用被铁凋亡诱导剂消除，但被铁凋亡抑制剂和PERK敲除所模仿。研究表明，PERK结构，而不是其激酶活性（用抑制激酶活性的K618A位点突变-ΔK质粒或PERK的蛋白C末端敲除-ΔC质粒转染），在乙醇暴露期间介导增强的MAMs形成和铁凋亡。
结论：槲皮素通过调节PERK依赖性MAMs的形成，抑制铁凋亡，从而改善乙醇诱导的肝损伤。
