Dynamic regulators of ferroptosis: Post-translational modifications in ferroptotic cell death

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, plays a critical role in various pathological conditions, including cancer and organ injury. Post-translational modifications (PTMs) dynamically regulate ferroptosis by modulating the stability, activity, and interactions of key proteins such as GPX4, SLC7A11, and ACSL4. A single protein can undergo multiple PTMs, and the same regulatory enzyme may exert opposing effects on ferroptosis by modifying different proteins. Therefore, a comprehensive analysis of PTMs in regulatory proteins is essential for elucidating their overall impact on ferroptosis. This review systematically examines the roles of ubiquitination, ubiquitin-like modifications (e.g. UFMylation, SUMOylation), alkylation, and succination in ferroptosis regulation. We highlight how E3 ligases, deubiquitinating enzymes (DUBs), and other PTM-associated enzymes modulate ferroptosis by governing the degradation or stabilization of key targets, thereby influencing redox homeostasis and iron metabolism. Clinically, PTM-targeting agents, including E3 ligase modulators and SUMOylation inhibitors, demonstrate therapeutic potential in preclinical models, though their clinical translation remains in its early stages. This review underscores the complexity of PTM-mediated ferroptosis regulation and highlights the need to explore PTM crosstalk, refine therapeutic strategies, and develop novel PTM modulators for the treatment of malignancies and iron-related disorders.