The impact of lipid metabolism on ferroptosis in myocardial ischemia-reperfusion injury.

Abstract

Myocardial ischemia-reperfusion (I/R) injury remains a major challenge in cardiovascular interventions. Although conventional reperfusion therapies restore coronary blood flow, they can often exacerbate myocardial damage. In recent years, ferroptosis, a novel form of regulated cell death characterized by iron-dependent lipid peroxidation, has emerged as a pivotal contributor to myocardial I/R injury. Unlike apoptosis and necrosis, ferroptosis is driven by the accumulation of reactive iron and the peroxidation of membrane phospholipids enriched with polyunsaturated fatty acids (PUFAs), processes that are tightly regulated by lipid metabolism. However, the precise mechanisms linking lipid metabolic reprogramming to ferroptosis during myocardial I/R injury remain incompletely understood. To address this gap, this review systematically examines the interplay between lipid metabolism and ferroptosis in myocardial I/R injury. We highlight the roles of fatty acid uptake, β-oxidation, phospholipid remodeling, cholesterol metabolism, and mitochondria-lipid droplet interactions in forming a deleterious cycle of metabolic disruption, oxidative stress, and membrane damage. Key regulators, such as acyl-CoA synthetase long-chain family member 4 (ACSL4), lysophosphatidylcholine acyltransferase 3 (LPCAT3), and cluster of differentiation 36 (CD36), are emphasized for their roles in contributing to ferroptotic vulnerability. Moreover, the review also explores the protective roles of short-chain fatty acids (SCFAs) and 7-dehydrocholesterol (7-DHC) as emerging anti-ferroptotic agents. Novel yet understudied mechanisms with therapeutic potential are also discussed, including Rab8a-PLIN5-mediated lipid droplet trafficking and 7-DHC reductase (DHCR7) deficiency-induced 7-DHC accumulation. Collectively, this review provides a comprehensive framework for understanding the lipid metabolism-ferroptosis axis in myocardial I/R injury, offering insights for future mechanistic studies and clinical translation.