Ferroptosis-Based Cancer Therapy: Molecular Regulation, Resistance Mechanisms, and Combination Strategies

Ferroptosis is a regulated form of cell death driven by iron-dependent peroxidation of polyunsaturated phospholipids in cellular membranes. Since the term was introduced in 2012, the field has moved quickly from a chemical curiosity observed in RAS-mutant cell lines to a recognised vulnerability across many tumour types. Cancer cells that are mesenchymal, drug-tolerant or metabolically rewired often depend heavily on the glutathione peroxidase 4 (GPX4) axis and on parallel antioxidant systems, and this dependency can be exploited pharmacologically. This review summarises the biochemical core of ferroptosis, including iron handling, phospholipid remodelling and the GPX4, FSP1, GCH1 and DHODH defence systems. We then discuss how oncogenic and tumour-suppressor pathways such as p53, BAP1, NRF2 and Hippo signalling tune sensitivity, and how cancer cells escape ferroptosis through transcriptional, metabolic and microenvironmental adaptation. Pharmacological strategies are surveyed, from system xc− inhibition to covalent GPX4 inhibitors, with emphasis on the limits of the currently available compounds. Combination approaches with chemotherapy, targeted therapy, radiotherapy and immunotherapy are examined, along with the conflicting evidence on how ferroptotic cells shape antitumour immunity. Finally, we consider candidate biomarkers for patient selection, the obstacles to clinical translation, and research priorities. We argue that progress will depend less on discovering further inducers than on defining which tumours are truly ferroptosis-prone and on delivering inducers with acceptable selectivity.