Background <p>Colon cancer (CC) is a malignant cancer with high incidence and poor prognosis.Ferroptosis could induce iron-dependent accumulation of lipid peroxidation and oxidative death of cancer cells. This work aimed to elucidate the role of KAT6A, a lysine acetyltransferase, in CC development.</p> Methods <p>We collected tumor and paired non-tumor samples from patients with CC and analyzed the RNA and protein level of KAT6A using quantitative real-time PCR and immunohistochemistry (IHC) staining. We conducted KAT6A knockdown in CC cells and determined cell proliferation and ferroptosis. Cell proliferation was measured by cell counting kit-8 (CCK-8) and colony formation assay. Ferroptosis was identified by measuring the levels of lipid ROS, intracellular iron and Fe²⁺, malondialdehyde (MDA), and glutathione (GSH). The in vivo effects of KAT6A were assessed by xenograft mouse model. Protein levels of KAT6A and glutathione peroxidase 4 (GPX4) were checked by western blotting assay. The enticement of acetylation on lysine 9 of histone3 (H3K9ac) and RNA polymerase II on GPX4 gene was analyzed by chromatin immunoprecipitation (ChIP) assay.</p> Results <p>The RNA and protein level of KAT6A is notably higher in tumor tissues compared with the non-tumor sections. Depletion of KAT6A suppressed in vitro and in vivo CC cell growth. Overexpression of KAT6A reversed the erastin-induced CC cell death. knockdown of KAT6A significantly elevated the intracellular level of MDA, induced accumulation of total iron, Fe²⁺ and lipid ROS, and suppressed the level of GSH. The knockdown of KAT6A caused a decrease in the expression of GPX4 and enrichment of H3K9ac on GPX4 gene.</p> Conclusion <p>KAT6A promotes the proliferation of CC cells and suppresses ferroptosis via epigenetic regulation of GPX4. Our work presented KAT6A as a potential diagnostic and therapeutic target for treatment CC.</p>