Medicinal plants and ferroptosis in cancer: Emerging evidence and therapeutic opportunities

Abstract

Ferroptosis is an iron-dependent type of regulated cell death characterized by excessive lipid peroxidation, loss of cellular antioxidant defenses, and buildup of redox-active iron. In contrast to apoptosis, ferroptosis is closely linked to iron metabolism, depletion of glutathione (GSH), inactivation of glutathione peroxidase 4 (GPX4), and oxidative damage to membrane lipids containing polyunsaturated fatty acids. Since malignant cells often show heightened iron requirements, altered lipid metabolism, and increased oxidative stress, ferroptosis has become a promising therapeutic vulnerability in cancer. Medicinal plants serve as a significant reservoir of structurally diverse compounds that can regulate these pathways. A growing body of experimental evidence shows that artemisinin and its derivatives, curcumin, quercetin, sulforaphane, and other phytochemicals can trigger ferroptotic cancer-cell death by altering iron homeostasis, ferritin degradation, system Xc− activity, GPX4, GSH metabolism, reactive oxygen species generation, and lipid peroxidation. Artemisinin derivatives can raise intracellular labile iron via ferritin degradation, thereby sensitizing tumor cells to ferroptosis. Curcumin has been demonstrated to induce ferroptosis in breast cancer models through iron accumulation, lipid peroxidation, and modulation of ferroptosis-associated signaling. Quercetin drives lysosomal ferritin degradation and iron-dependent lipid peroxidation, while sulforaphane can promote SLC7A11 degradation and ferroptosis in osteosarcoma. Despite these encouraging findings, the evidence remains largely preclinical. Poor bioavailability, chemical instability, absence of standardized botanical preparations, tumor selectivity, and inadequate clinical validation continue to be major obstacles. This review critically assesses the molecular link between medicinal plants and ferroptosis in cancer and explores opportunities for combination therapy, nanotechnology, and precision oncology.