Enzymatic Regulation of Ferroptosis: Molecular Mechanisms, Metabolic Interactions, and Therapeutic Opportunities: A Comprehensive Review

Abstract

Ferroptosis is an iron-dependent modality of regulated cell death precipitated by the liberated accumulation of phospholipid hydroperoxides within cellular membranes, and it is a precisely enzyme-governed metabolic system of considerable pathophysiological consequence across oncology, neurodegeneration, and inflammatory disease. While mechanistic discoveries around ferroptosis biology have rapidly proliferated, little is known about how enzymatic interplay ultimately regulates ferroptotic responses. This review aims to fill this gap by integrating these diverse components into a unified model, in which ferroptotic susceptibility is not determined solely by GPX4 but rather a functionally redundant, hormonally regulatable pool of parallel antioxidant and execution enzymes whose balance ultimately governs cell fate. By critically evaluating the translational potential of these axes and the evidence-based controversies that remain, particularly concerning enzymatic vs. autoxidative lipid peroxidation and recent editorial objections to some studies, we identify opportunities for co-targeting ferroptosis with immunotherapeutic, hormonal, or metabolic approaches in actionable combinatorial strategies while stressing the urgent need for validation of relevant in vivo biomarkers to advance their clinical translation.