The dual role of lipid peroxidation: from cellular signaling to disease pathogenesis

Lipid peroxidation (LPO) has traditionally been regarded as a damaging consequence of oxidative stress; however, accumulating evidence indicates that it also participates in context-dependent cellular signaling. This review summarizes the biochemical foundations of LPO, including the kinetics of free-radical chain reactions, substrate specificity, and the biological activities of key oxidation products such as 4-hydroxynonenal and malondialdehyde. Under tightly regulated conditions, LPO-derived metabolites contribute to cell-cycle regulation, immune and inflammatory signaling, and potentially physiological ferroptotic cell turnover. In contrast, excessive or persistent LPO promotes cellular injury through covalent modification of proteins and lipids, mitochondrial dysfunction, proteostasis disruption, regulated cell death, and remodeling of local tissue microenvironments. These mechanisms have been implicated in the development and progression of neurodegenerative disorders, metabolic diseases, atherosclerosis, and malignancies. In cancer, the effects of LPO are strongly influenced by concentration and cellular context: extensive lipid peroxide accumulation can promote tumor cell death, whereas sublethal LPO may activate adaptive antioxidant signaling and support proliferative and invasive phenotypes, metastatic potential, and treatment resistance in selected contexts. This context dependence may partly explain the limited and inconsistent clinical benefits of conventional broad-spectrum antioxidant approaches. Accordingly, more selective modulation of LPO-related enzymes and defense systems, including lipoxygenases and glutathione peroxidase 4, has emerged as a potential therapeutic strategy. Nanotechnology-enabled delivery platforms may further improve the spatial and temporal control of such interventions; nevertheless, most of these approaches remain at preclinical or early translational stages and continue to face challenges related to safety, pharmacokinetics, target specificity, and disease-dependent therapeutic windows. By integrating fundamental molecular mechanisms with emerging therapeutic strategies, this review provides a balanced framework for understanding the dual biological roles of LPO and for informing the future development of more precise LPO-targeted interventions.