Post-translational modifications in ferroptosis: mechanisms and therapeutic potential

Ferroptosis has been demonstrated to play pivotal roles in a spectrum of pathological processes, including multi-organ dysfunction, retinal degeneration, neurodegenerative disorders, autoimmune diseases, and tumorigenesis. Notably, its pivotal role in counteracting cancer drug resistance positions ferroptosis as a promising therapeutic target. The precise regulation of this cell death pathway is fundamentally dependent on the functional orchestration of associated proteins, where subtle modifications can exert profound effects on ferroptotic progression. Post-translational modifications (PTMs) serve as sophisticated molecular switches that dynamically regulate protein structure, activity, subcellular localization, and functional interactions through covalent attachment of biochemical groups or regulatory subunits. These modifications - including proteolytic processing, partial degradation, or complete protein turnover - significantly expand the functional repertoire of the proteome, thereby exerting crucial regulatory control over cellular survival decisions. This comprehensive review systematically examines the intricate crosstalk between ferroptosis and major PTM pathways, with particular emphasis on ubiquitination, phosphorylation, acetylation, SUMOylation, methylation, oxidative modifications, glycosylation, S-nitrosylation, lactylation, and lipidation. Through critical analysis of current research advances, we elucidate the mechanistic basis by which PTMs modulate ferroptotic pathways and discuss their therapeutic implications. Furthermore, we provide prospective insights into emerging research directions and potential clinical applications targeting PTM-mediated ferroptosis regulation.