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

CBX3 deletion increases intracellular ROS and lipid ROS after ferroptosis induction, sensitizing colorectal cancer cells to ferroptosis particularly under IFNγ stimulation in vitro and in MC38 tumors in vivo.

• Why it matters: System Xc- (SLC7A11/SLC3A2) helps tumors resist ferroptosis by maintaining redox balance, but how epigenetic control of this axis affects IFNγ-linked sensitivity is unclear.
• What they did: Using human CRC cells and MC38 syngeneic tumors, the study combined ferroptosis induction with IFNγ, performed RNA-seq to find an 11-gene oxidative stress signature, and mapped CBX3 direct promoter targets for Slc7a11 and Slc3a2.
• The result: The 11-gene oxidative stress signature is downregulated in Cbx3KO tumors after combined treatment and low expression correlates with improved overall survival; CBX3 loss reduces RNA polymerase II recruitment to SLC7A11/SLC3A2, an effect worsened by IFNγ but restored by STAT1 deletion.