Oxidized phospholipids: evolution, signaling, cell death, and human diseases

Oxidized phospholipids (OxPLs) represent a class of molecules generated during evolution that shift from fundamental membrane building-blocks to key signaling mediators, linking lipid metabolism, cellular redox homeostasis and multi-faceted cell-fate control. Generated by both enzymatic and non-enzymatic peroxidation events, OxPLs engage in extensive signaling crosstalk with lyso-phospholipids and oxylipins. The FerroLipid framework describes iron-lipid peroxidation crosstalk to contextualize iron-dependent lipid signaling. OxPLs govern diverse regulated cell-death programs: they act as lipid death signals in apoptosis and ferroptosis, tune ferroptotic outputs through intrinsic antioxidant systems, and exert context-specific modulatory effects on pyroptosis and other cell-death modalities. Beyond cell-death execution, OxPLs signal through pattern-recognition, scavenger and nuclear receptors to orchestrate inflammation, membrane remodeling, phagocytic clearance, autophagy, mitophagy and protein homeostasis. Threshold-dependent accumulation of OxPLs drives pathological processes across neurodegenerative, metabolic, cardiovascular, neoplastic and infectious diseases; their disease-specific molecular signatures confer potential as both diagnostic biomarkers and therapeutic targets. Redox phospholipidomics coupled with mass-spectrometry imaging enables accurate, species-resolved profiling of distinct OxPL species. Multiple pharmacological approaches and gene-editing interventions have demonstrated tangible translational prospects for OxPL-oriented therapy. This review synthesizes existing knowledge of OxPL biology from evolutionary origins and signaling mechanisms to disease relevance, analytical tools and therapeutic opportunities. It highlights major unresolved research bottlenecks and provides a solid conceptual foundation for advancing lipid-targeted treatments for complex human disorders.