Marine-Food-Derived Ether Phospholipids Mitigated Alcoholic Liver Disease by Preferably Suppressing Lipid Peroxidation rather than Ferroptosis Defense

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.