Natural products as modulators of ferroptosis: Therapeutic implications and molecular mechanisms in disease treatment.

Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxide accumulation and is implicated in the pathogenesis of various diseases, including cancer, neurodegenerative disorders, diabetes, and cardiovascular diseases. Natural products, with their unique chemical scaffolds and multitarget pharmacological effects, have recently been recognized as potent modulators of ferroptosis, offering promising drug-like properties. This review comprehensively summarizes the molecular mechanisms underlying ferroptosis, encompassing iron metabolism, lipid peroxidation, and the SLC7A11-GSH-GPX4 antioxidant axis, and systematically categorizes natural products such as terpenoids, flavonoids, alkaloids, saponins, and polyphenols based on their structural classes and mechanisms of action. These compounds modulate ferroptosis through various pathways, including iron chelation, ROS regulation, and key protein interactions, demonstrating efficacy in both experimental and preliminary clinical settings across a spectrum of diseases. In oncology, natural compounds can sensitize tumors to chemotherapy and overcome drug resistance by activating ferroptotic cell death. Conversely, their antiferroptotic actions protect against tissue injury in nononcological diseases such as neurodegenerative conditions, metabolic disorders, and organ injury. Nevertheless, their application remains limited by restricted availability, compositional complexity, and unstable pharmacokinetic features. Advances in nano-delivery systems and synthetic biology are highlighted as promising strategies to overcome these barriers. Overall, natural products represent a valuable resource for developing novel ferroptosis-targeting therapies, with significant implications for future drug discovery and therapeutic innovation in a wide range of human diseases.