Beyond antioxidants: Context-selective reprogramming of ferroptosis by natural polyphenols in chronic disease intervention

Chronic diseases, with a focus here on non-cancerous conditions including cardiovascular, metabolic, neurological, and musculoskeletal disorders, as well as other relevant conditions, share pathological characteristics, such as persistent oxidative stress, reduced metabolic flexibility, and progressive tissue degeneration. Ferroptosis, an iron-dependent cell death triggered by lipid peroxidation, is now recognized as a critical factor in these pathological processes. Natural polyphenols, derived from plant sources, exhibit antioxidant and anti-inflammatory properties and demonstrate potential in regulating ferroptosis-related signaling pathways. This review systematically explores the molecular crosstalk between ferroptosis and polyphenols across major chronic diseases, highlighting their therapeutic and translational potential. Specifically, it elucidates the regulatory role of polyphenols in iron homeostasis, the inhibition of lipid peroxidation, and the restoration of redox balance, thus uncovering novel opportunities for dietary or pharmacological interventions targeting ferroptosis. Elucidating this interaction underscores the therapeutic potential of natural polyphenols as an innovative strategy for the prevention and treatment of chronic diseases.