Lycopene as a multi-target inhibitor of ferroptosis: A narrative review of preclinical evidence and clinical prospects.

This narrative review examines lycopene, a natural carotenoid found in tomatoes and other fruits, as a multi-target inhibitor of ferroptosis - an iron-dependent form of regulated cell death driven by lipid peroxidation. Preclinical evidence indicates that lycopene suppresses ferroptosis through four complementary mechanisms: activation of the Nrf2/GPX4 antioxidant axis, inhibition of ferritinophagy via NCOA4 downregulation, inhibition of CYPOR (reducing hydrogen peroxide production), and direct scavenging of lipid peroxyl radicals. The therapeutic potential of lycopene is evaluated in polycystic ovary syndrome (PCOS), non-alcoholic steatohepatitis (NASH), neurodegenerative disorders, cancer, cardiovascular diseases, and injuries induced by environmental toxicants including atrazine, cadmium, cisplatin, and cyclophosphamide. Despite promising preclinical findings, significant limitations preclude clinical translation: poor oral bioavailability, lack of identified direct molecular targets, absence of large-scale clinical trials, sex bias in animal studies, and publication bias. The proposed dual role of lycopene in cancer (inducing ferroptosis in malignant cells while inhibiting it in normal cells) remains an unproven hypothesis requiring direct experimental testing. Future research priorities include developing bioavailable formulations, conducting target identification studies, and validating ferroptosis-specific biomarkers. Currently, the primary contribution of lycopene research remains in mechanistic preclinical studies, and clinical recommendations are premature.