Ferroptosis Resistance: Redundant Antioxidant Networks Is a Barrier to Cancer Therapy

Ferroptosis is an iron-dependent, lipid peroxidation–driven form of regulated cell death that has emerged as a promising strategy to eliminate therapy-resistant cancers. However, both intrinsic and acquired resistance to ferroptosis-inducing agents (FINs) limit their clinical efficacy. From this perspective, an integrated model is proposed in which ferroptosis resistance emerges through coordinated redox, metabolic, and transport adaptations that collectively suppress lipid peroxidation and support tumor cell survival. Central to this defense is the cysteine–glutathione–glutathione peroxidase 4 (GPX4) axis, supported by parallel CoQ10-dependent antioxidant systems including ferroptosis suppressor protein 1 (FSP1), dihydroorotate dehydrogenase (DHODH), NAD(P)H quinone oxidoreductase 1 (NQO1), and the GCH1–tetrahydrobiopterin (BH4) pathway. These systems are further reinforced by NrF2-mediated transcriptional programs, iron sequestration and export mechanisms, lipid remodeling that limits polyunsaturated fatty acid availability, and ATP-binding cassette (ABC) transporters that regulate drug and glutathione flux. Tumor heterogeneity—including differences in differentiation state, epithelial–mesenchymal plasticity, and metabolic reprogramming—generates subpopulations with distinct ferroptosis sensitivities and facilitates therapeutic escape. Emerging strategies that simultaneously target multiple resistance nodes, including GPX4 or FSP1 inhibition, combination chemotherapy, and nanoparticle-based delivery systems, may enhance ferroptosis-based therapies. A deeper understanding of oxidant–antioxidant networks governing ferroptosis resistance will enable the rational design of next-generation anticancer strategies to overcome drug resistance.