Histone Post-Translational Modifications Regulating Ferroptosis: The Molecular Mechanisms and Disease Associations

Ferroptosis is a form of programmed cell death characterized by iron-dependent phospholipid peroxidation and is implicated in a wide range of human diseases. Emerging evidence highlights the critical role of epigenetic regulation in this process. Dysregulation of histone post-translational modifications (HPTMs) is increasingly recognized as a pivotal mechanism linking metabolic reprogramming to various pathological conditions. HPTMs constitute one of the key epigenetic regulatory mechanisms and mediate ferroptosis by modulating the transcription of core ferroptosis-related genes. This review systematically summarizes site-specific HPTMs, including histone methylation, acetylation, ubiquitination, phosphorylation, lactylation, and β-hydroxybutyrylation. Furthermore, we elucidate how infectious diseases, tumors, and chronic non-infectious conditions drive disease progression via HPTMs-dependent regulation of ferroptosis. A comprehensive dissection of these epigenetic regulatory networks may facilitate the development of combinatorial therapeutic strategies targeting HPTMs and ferroptosis inducers, thereby providing new insights into the treatment of ferroptosis-associated disorders.