HDAC inhibitors as ferroptosis sensitizers in cancer: Epigenetic regulation of redox balance and iron metabolism

The evasion of programmed cell death significantly contributes to therapeutic failure in cancer, with resistance to apoptosis being the most prevalent form of resistance in multidrug-refractory diseases. Ferroptosis, an iron-dependent, non-apoptotic form of regulated cell death characterized by the lethal accumulation of lipid peroxides, represents a pharmacologically significant vulnerability in cancers that are resistant to apoptosis and tolerant to drugs. The resistance to ferroptosis, induced by the aberrant overexpression of the epigenetic enzyme histone deacetylases (HDACs) and the sustained transcriptional activity of key antiferroptotic targets, particularly GPX4 and SLC7A11, is enforced through epigenetic mechanisms. This review examines the extant preclinical and translational data, demonstrating that HDAC inhibitors predispose cancer cells to ferroptosis through four mechanistically convergent pathways. These pathways include the transcriptional silencing of SLC7A11 and subsequent glutathione depletion, disruption of intracellular iron homeostasis via ferroportin downregulation, enhancement of mitochondrial ROS-induced lipid peroxidation, and suppression of the HDAC3-NRF2-GPX4 antiferroptotic axis. The specific roles of HDAC1, HDAC3, and HDAC10 in colorectal, lung, gastric, and hematological cancers are elucidated. Additionally, the review discusses hybrid molecules of HDAC-ferroptosis, combination strategies with GPX4 inhibitors, and immunochemotherapy. Considerations such as isoform selectivity, biomarker development, and clinical translation are addressed, highlighting HDAC inhibitor-mediated ferroptosis sensitization as a promising strategy to overcome drug resistance in cancer. See also the graphical abstract(Fig. 1).