Genetic mutations governing ferroptosis sensitivity and resistance: a precision approach to cancer therapy

Ferroptosis, an iron-dependent programmed cell death pathway driven by lipid peroxidation, offers a transformative approach to cancer therapy by exploiting unique cellular vulnerabilities. This comprehensive review elucidates the intricate molecular mechanisms of ferroptosis and their modulation by genetic mutations across diverse malignancies, including lung, hematological, liver, colorectal, breast, glioma, renal, pancreatic, thyroid, prostate, cervical, gastric, and melanoma. We delineate the critical functions of ferroptosis regulators, such as GPX4, system Xc⁻, and iron metabolism proteins, in orchestrating the delicate balance between oxidative damage and antioxidant protection. The study further examines how oncogenic mutations in genes like EGFR, KRAS, TP53, KEAP1, and IDH1 reshape ferroptosis susceptibility or resistance through alterations in metabolic pathways, redox homeostasis, and tumor microenvironment interactions. By highlighting mutation-specific sensitivities, this work underscores the potential of ferroptosis-targeted strategies to surmount therapeutic resistance, synergize with conventional treatments like chemotherapy and immunotherapy, and drive precision oncology forward, paving the way for enhanced clinical outcomes across a broad spectrum of cancers.