Transcriptional and epigenetic regulation of ferroptosis in cancer drug resistance: Mechanisms and targeted therapeutic opportunities.
Ferroptosis, an iron-dependent form of regulated cell death driven by excessive lipid peroxidation, has emerged as a critical determinant of cancer drug resistance. While significant progress has been made in understanding the core biochemical pathways of ferroptosis, the transcriptional and epigenetic mechanisms governing ferroptosis sensitivity in drug-resistant cancer cells remain incompletely understood. This review provides a comprehensive analysis of the transcriptional regulatory networks (Nrf2, YY1, p53, HIF-1α) and epigenetic modifications (DNA methylation, histone modifications, non-coding RNAs, chromatin remodeling) that orchestrate ferroptosis programs in drug resistance. Critically, we propose that transcriptional-epigenetic crosstalk represents the core driver of ferroptosis plasticity, enabling cancer cells to dynamically adapt to therapeutic stress. We integrate our team's original findings on YY1/YY2 homeostatic regulation of ferroptosis in colorectal cancer drug resistance and discuss the dual role of ferroptosis-both lethal and sublethal-in shaping tumor evolution and therapeutic outcomes. Furthermore, we systematically analyze preclinical and clinical progress in targeting transcriptional and epigenetic regulators to sensitize drug-resistant cancers to ferroptosis, highlighting rational combination strategies and major clinical translation bottlenecks. Finally, we propose five concrete future research directions that will advance the development of ferroptosis-based precision cancer therapy. This review bridges mechanistic epigenetic biology with translational pharmacology, providing a valuable reference for overcoming cancer drug resistance.