Redox mechanism of glycerophospholipids and relevant targeted therapy in ferroptosis

Ferroptosis, an iron-dependent form of regulated cell death driven by redox dysregulation, is defined by iron overload, reactive oxygen species overproduction, and subsequent peroxidation of polyunsaturated fatty acid-containing phospholipids, notably glycerophospholipids. This review comprehensively delineates the enzymatic such as lipoxygenases and non-enzymatic including Fenton reaction pathways governing glycerophospholipid peroxidation. Furthermore, we systematically dissect fine regulation of iron ions, including absorption, transport, and redox state transition. Given pathophysiological relevance of ferroptosis to numerous diseases, especially neurodegenerative disorders and various cancers, we evaluate emerging therapeutic strategies targeting key ferroptosis nodes, with a primary focus on the key enzymes involved in lipid peroxidation, transferrin receptor-mediated endocytosis mechanism and traditional Chinese medicine. Our work provides a direction for advancing ferroptosis research and developing combinatorial therapies that synergize ferroptosis induction with conventional treatments.