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

Abstract

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.