Non-Enzymatic Lipid Peroxidation in Cancer Biology: An Overview

Cancer is characterized by a disrupted redox balance and impaired antioxidant defense, leading to the excessive production of reactive oxygen species (ROS) and oxidative stress. While moderate levels of ROS support tumor growth and adaptation, excessive oxidative stress induces lipid peroxidation (LPO), a self-catalyzed chain reaction that destroys cell membranes and generates reactive aldehydes. Among such reactive aldehydes, 4-hydroxynonenal (HNE) is considered a second messenger of ROS, exerting concentration- and context-dependent effects on cell proliferation, differentiation, apoptosis, immune modulation, and cell death. Since cancer cells are typically more sensitive to the cytotoxicity of HNE, it may also be considered not only a cofactor in carcinogenesis but also a natural factor in the organism's defense against cancer. This paper provides a comprehensive overview of non-enzymatic LPO in cancer, highlighting its dual role in tumor promotion and suppression. We discuss how persistent oxidative stress, metabolic reprogramming, and remodeling of the tumor lipidome shape LPO dynamics and ferroptosis susceptibility within the tumor microenvironment, as well as the emerging therapeutic strategies that exploit LPO. Therefore, exploring the advantage of LPO's dualistic nature may help to develop more individualized and efficient integrative biomedicine anticancer treatments.