Geno-guided targeting of ferroptosis: a multi-layered network to overcome radioresistance in lung cancer

Lung cancer is one of the most prevalent and lethal malignancies worldwide, and radiotherapy serves as a standard therapeutic modality for the management of advanced or inoperable non-small cell lung cancer. However, radioresistance remains a major obstacle that compromises therapeutic efficacy and drives tumor recurrence. Ferroptosis—an iron-dependent, lipid peroxidation-governed form of regulated cell death—substantially contributes to radiation-mediated tumor cell elimination. This review establishes a multi-layered regulatory network through which ferroptosis mediates radioresistance in lung cancer, spanning genetic mutations, epigenetic and RNA-based regulation, protein post-translational modifications, and lipid metabolism reprogramming. Unlike existing reviews, this paper stratifies ferroptotic vulnerability and radiosensitivity according to common driver genotypes—including TP53, LKB1and KEAP1—and proposes a genotype-guided paradigm for precise radiosensitization. By integrating these molecular layers, review provides a supplementary theoretical framework for optimizing radiotherapy in lung cancer and highlights how targeting ferroptosis can overcome resistance in a mutation-specific manner. Furthermore, the crosstalk between ferroptosis and cuproptosis represents a promising combinatorial therapeutic avenue that warrants further preclinical and clinical investigation.