Liu Yanjun, Wu Yuan, Liu Bin, Wang Xiaoxu, Meng Nan, Song Yu, Xue Changhu, Xu Jie
State Key Laboratory of Marine Food Processing and Safety Control, College of Food Science and Engineering, Ocean University of China, Qingdao 266404, China.
Sanya Ocean Institute, Ocean University of China, Sanya 572000, China.
J Agric Food Chem. 2025 Jul 2;73(26):16627-16635. doi: 10.1021/acs.jafc.5c03505. Epub 2025 Jun 13.
Alcoholic liver disease (ALD) is one of the leading causes of liver-related mortality and poses a major global health burden. Ether phospholipids have emerged as novel candidates in protecting against alcoholic liver disease based on their unique structural and functional properties. In this study, we proposed that dietary ether phospholipids, particularly plasmenyl phosphatidylethanolamine (PlsEtn) and plasmanyl phosphatidylcholine (PakCho) derived from sea cucumber, demonstrate potent hepatoprotective activity against ALD by the inhibition of ferroptosis. In the murine model of ALD, PlsEtn and PakCho attenuated ethanol-induced liver injury, evidenced by reduced lipid accumulation and suppressed ferroptotic hallmarks, including lipid peroxidation and iron dysregulation. Mechanistically, PlsEtn and PakCho act as radical-trapping antioxidants, intercepting peroxidation cascades upstream of ferroptosis initiation. Besides, the treatment with PlsEtn and PakCho restored mitochondrial function and rebalanced redox homeostasis. Additionally, PlsEtn and PakCho suppressed ferritin heavy chain 1 (Fth1)-mediated iron storage and inhibited endosomal iron release and transport, thereby intercepting iron-driven lipid peroxidation chain propagation. Crucially, their antiferroptotic efficacy operates independently of canonical GPX4 pathways, contrasting with pro-ferroptotic endogenous ether lipids. Our findings unveil marine-food-derived ether phospholipids as novel dietary modulators of ferroptotic damage, offering a dietary strategy for ALD.
酒精性肝病（ALD）是肝脏相关死亡率的主要原因之一，给全球健康带来了重大负担。基于其独特的结构和功能特性，醚磷脂已成为预防酒精性肝病的新型候选物质。在本研究中，我们提出，膳食醚磷脂，特别是源自海参的缩醛磷脂酰乙醇胺（PlsEtn）和缩醛磷脂酰胆碱（PakCho），通过抑制铁死亡对ALD具有强大的肝脏保护活性。在ALD小鼠模型中，PlsEtn和PakCho减轻了乙醇诱导的肝损伤，脂质积累减少以及铁死亡特征（包括脂质过氧化和铁失调）受到抑制证明了这一点。从机制上讲，PlsEtn和PakCho作为自由基捕获抗氧化剂，在铁死亡起始的上游拦截过氧化级联反应。此外，用PlsEtn和PakCho处理可恢复线粒体功能并重新平衡氧化还原稳态。此外，PlsEtn和PakCho抑制铁蛋白重链1（Fth1）介导的铁储存，并抑制内体铁的释放和运输，从而拦截铁驱动的脂质过氧化链的传播。至关重要的是，它们的抗铁死亡功效独立于经典的GPX4途径发挥作用，这与促铁死亡的内源性醚脂形成对比。我们的研究结果揭示了海洋食物来源的醚磷脂是铁死亡损伤的新型膳食调节剂，为ALD提供了一种饮食策略。
