CBX3 Deletion Overcomes Ferroptosis Resistance in Colorectal Cancer by Targeting IFNγ/SLC7A11/SLC3A2 Axis

System Xc⁻ (SLC7A11/SLC3A2) maintains redox balance by supporting glutathione synthesis, thereby preventing lipid peroxidation and ferroptosis, and represents a promising therapeutic target in cancer. In this work, we revealed that an important epigenetic regulator, CBX3 deletion significantly increased intracellular ROS and lipid ROS level following ferroptosis inducing, particularly under IFNγ stimulation, thereby sensitized CRC cells to ferroptosis in vitro using human CRC cells as well as in vivo using MC38 syngenetic tumors. RNAseq with mice syngeneic tumors revealed an 11-gene oxidative stress signature downregulated in Cbx3KO tumors after combined treatment; its low expression score correlated with improved overall survival in CRC patients. Among them, Slc7a11, Ptgs2, and Cth were identified as CBX3 direct target genes. Additionally, several amino acid transporters functionally coupled to Xc- antiporter, as Slc3a2, Slc7a5, Slc1a5 and Slc6a9, all significantly decreased in Cbx3KO tumor under RSL3+IFNγ treatment. Mechanistically, CBX3 binds directly to the promoter of Slc7a11 or Slc3a2 to sustain their expression and redox balance to resist ferroptosis in CRC. Knockout of CBX3 in CRC cells significantly impaired RNA polymerase II recruitment to the promoter of SLC7A11 or SLC3A2 and reduced SLC7A11 and SLC3A2 expression, an effect that was further exacerbated under IFNγ stimulation but restored by STAT1 deletion. Overall, CBX3 protects CRC from oxidative stress by maintaining the functional integrity of IFNγ/STAT1/SLC7A11/SLC3A2 axis, positioning CBX3 as a potential therapeutic target for enhancing ferroptosis therapies in CRC.