Lipid Metabolism and Ferroptosis in Cancer: Regulatory Mechanisms, Alternative Splicing, and Therapeutic Implications

Ferroptosis is an iron-dependent form of regulated cell death driven by phospholipid peroxidation and is increasingly recognized as an important vulnerability in cancer. Its sensitivity is determined by the interplay between membrane lipid composition, iron availability, oxidative stress, and antioxidant defense. Cancer cells can adapt to these pressures by altering the balance between polyunsaturated and monounsaturated fatty acids, thereby shifting toward either ferroptosis sensitivity or resistance. Emerging evidence indicates that alternative splicing provides an additional regulatory layer by generating functionally distinct isoforms of genes involved in cystine transport, iron metabolism, oxidative stress, antioxidant protection, and lipid remodeling. Functionally validated splice events affecting the cystine/glutamate antiporter subunit, transferrin receptor, spermidine/spermine acetyltransferase 1, SCL/TAL1 interrupting locus protein, and cluster of differentiation 44 demonstrate that isoform switching can influence ferroptotic susceptibility independently of total gene expression. This review integrates current knowledge on the biochemical basis of ferroptosis, the lipid determinants of ferroptosis sensitivity, and splicing-dependent mechanisms that shape vulnerability and resistance in cancer. Therapeutic strategies targeting ferroptosis defense systems, lipid metabolism, and alternative splicing are also discussed. Finally, we highlight the potential of integrating long-read ribonucleic acid sequencing, lipidomics, proteomics, and functional ferroptosis assays to develop multidimensional vulnerability signatures for patient stratification and precision cancer therapy.