Ferroptosis and Lipid Peroxidation: Mechanisms, Regulation, and Disease Relevance

Ferroptosis, an iron-dependent form of regulated cell death driven by uncontrolled lipid peroxidation, has emerged as a central mechanism linking membrane lipid chemistry to cell fate decisions. Polyunsaturated fatty acid-containing phospholipids are preferentially oxidized during this process, and their accumulation compromises membrane integrity in ways that distinguish ferroptosis from apoptosis and other death pathways. Recent advances in lipidomics, redox biology, and iron metabolism now allow the enzymatic and non-enzymatic drivers of lipid peroxidation to be dissected with increasing precision, reshaping our understanding of degenerative disease, cancer biology, and tissue injury.Despite this progress, key questions remain open. It is still unclear how lipid peroxidation spreads between membranes and organelles, which phospholipid species and subcellular compartments are most vulnerable, and how cells integrate parallel defense systems to decide between survival and death. Answering these questions requires close collaboration between lipid biochemists, cell biologists, and disease-oriented researchers, and it calls for work that connects molecular mechanism to physiological and pathological outcomes.This Research Topic will focus on how lipid peroxidation is generated, propagated, and controlled at the membrane level, and how this shapes ferroptotic cell death in physiological and pathological contexts. We welcome contributions that:- Elucidate enzymatic and non-enzymatic drivers of lipid peroxidation, including lipoxygenases, cytochrome P450 oxidoreductase, and Fenton chemistry, and the reactive products they generate (e.g., MDA, 4-HNE).- Define regulatory networks controlling ferroptosis sensitivity, such as GPX4, FSP1/CoQ10, and GCH1/BH4 pathways, as well as upstream control by the cystine/glutamate antiporter system xc⁻.- Link membrane lipidomics and phospholipid remodeling (e.g., ACSL4, LPCAT3) to susceptibility or resistance to ferroptotic damage.- Explore iron metabolism, including iron uptake via transferrin, and its intersection with lipid peroxidation and organelle membrane function.- Apply pharmacological, biomarker, or novel imaging/methodological approaches to detect and modulate ferroptotic lipid damage in disease models (renal and cardiac disease, cancer, neurodegeneration, ischemia-reperfusion injury, metabolic disorders).- Contributions should provide mechanistic insight into the molecular basis of ferroptosis and lipid peroxidation. - Purely descriptive or clinical studies without a clear molecular perspective fall outside the scope of this collection.By integrating mechanistic, translational, and methodological perspectives, this collection aims to advance understanding of ferroptosis as both a membrane-lipid disease mechanism and a therapeutic target. In doing so, it seeks to bring together complementary expertise and to highlight how insights into membrane lipid oxidation can inform new strategies to detect, prevent, or treat ferroptosis-associated disease. Topic editors: ANA KARINA ARANDA, Gatikrushna Singh Source: https://www.frontiersin.org/research-topics/85792/ferroptosis-and-lipid-peroxidation-mechanisms-regulation-and-disease-relevance