Reconnoitering the role of Lipid Metabolites in Ferroptosis

• Biologically active lipids from natural sources hold significant promise in inducing ferroptosis, an iron-dependent form of programmed cell death that is driven by lipid peroxidation. • Marine-derived lipids can sensitize tumor cells to chemotherapy, improving cytotoxicity while sparing healthy tissues. • Natural lipid-based ferroptosis inducers show promise for enhancing cancer therapy efficacy. However, comprehensive research on their mechanisms, delivery, and safety is vital for clinical application and improving patient outcomes. • There is a need for further studies to understand the molecular mechanisms of ferroptosis induced by natural lipids, as well as the development of efficient and safe delivery systems to target cancer cells specifically. • Understanding these interconnected lipid pathways opens paths for therapeutic strategies, such as combining lipid-based therapies with conventional treatments. Targeting specific lipid metabolism pathways may enhance the efficacy of ferroptosis inducers and reduce the side effects of cancer treatments. Ferroptosis is a distinct form of regulated cell death driven by iron-dependent lipid peroxidation. It is different from other cell death forms like apoptosis, necrosis, and autophagy. Unlike apoptosis, ferroptosis is induced by the accumulation of reactive lipid peroxides and lacks the typical features of cell lysis. Ferroptosis is regulated through mechanisms involving iron accumulation and lipid peroxidation, primarily driven by lipoxygenases. Glutathione Peroxidase 4 (GPX4) plays a critical role by mitigating lipid hydroperoxide accumulation. The incorporation of polyunsaturated fatty acids into cellular membranes, facilitated by enzymes such as ACSL4 and LPCAT3, enhances susceptibility to ferroptosis. Ferroptosis is implicated in various pathological conditions, including cancer, neurodegenerative diseases, and ischemic injuries. This review explores the potential of lipid metabolites as ferroptosis inducers for cancer therapy. By synthesizing recent findings on the interplay between ferroptosis and lipid metabolism, this study highlights new research directions and therapeutic strategies across diverse diseases.