Abstract
Ferroptosis, an iron-dependent form of regulated cell death, represents an emerging therapeutic vulnerability in colorectal cancer (CRC). However, the epigenetic mechanisms controlling ferroptosis sensitivity in CRC remain poorly understood. Here, we identify histone deacetylase 3 (HDAC3) as a pivotal epigenetic suppressor of ferroptosis. Both pharmacological inhibition and genetic knockdown of HDAC3 significantly enhanced ferroptosis sensitivity, as evidenced by elevated intracellular ferrous iron (Fe2+) and lipid peroxidation. Mechanistically, inhibition of HDAC3 reduced the expression of nuclear factor erythroid 2-related factor 2 (NRF2), a master antioxidant transcription factor, thereby leading to downregulation of glutathione peroxidase 4 (GPX4), a central ferroptosis defense gene. Notably, NRF2 knockdown abolished GPX4 downregulation by HDAC3 inhibition, whereas GPX4 overexpression rescued the ferroptotic phenotype caused by HDAC3 depletion. Collectively, these findings define an HDAC3-NRF2-GPX4 axis that suppresses ferroptosis in CRC, and highlight HDAC3 as a potential therapeutic target for ferroptosis-based cancer treatment.