Epigenetic modifications in ferroptosis regulation of breast cancer

Breast cancer (BC) is the most frequently diagnosed type of cancer worldwide and has become the primary cause of cancer deaths in women, presenting many difficulties for treatment due to its molecular heterogeneity, dynamic tumor microenvironment and frequent development of resistance to traditional drugs and targeted therapies. Ferroptosis is a type of genetically regulated, iron-dependent cell death that occurs due to the extensive accumulation of phospholipid hydroperoxides, and it has been identified as an essential tumor-suppressive mechanism with significant implications for the pathogenesis, progression and treatment response of BC. Recent evidence shows that epigenetic mechanisms, including DNA methylation, histone post-translational modifications, and non-coding RNA-mediated regulation (microRNA, long non-coding RNA, circular RNA), precisely control the core ferroptosis machinery system Xc^-, GPX4, ACSL4, and FSP1 in a context-dependent manner. This review introduces the systematic and mechanistic integration of the current knowledge base on the modulation of BC cells' ferroptosis susceptibility by epigenetic reprogramming across molecular subtypes. We critically assess the preclinical and translational evidence linking specific epigenetic regulators to ferroptosis evasion, identify emerging biomarkers predictive of ferroptosis vulnerability, and discuss the therapeutic potential of epigenetic-ferroptosis co-targeting strategies to restore ferroptosis sensitivity, circumvent drug resistance, and enhance survival outcomes in patients with refractory or metastatic BC.