SALL4/ABCB6 Axis Suppresses Ferroptosis in Colon Cancer by Mediating Mitophagy

According to reports, the inhibition of ferroptosis is an essential culprit of malignant progression in various tumors, including colon cancer (CC). However, the relevant study on the regulatory mechanism of CC ferroptosis is sparse. This project was designed to identify the key genes modulating CC ferroptosis as well as specific mechanisms. Based on The Cancer Genome Atlas (TCGA)-CC mRNA expression data and immunohistochemistry assay, we analyzed the expression of ABCB6 and SALL4 in CC tissue. The HTFtarget was employed to predict the binding sites. The expression of ABCB6 and SALL4 in CC cells was analyzed by quantitative polymerase chain reaction, and the interaction between ABCB6 and SALL4 was verified by dual-luciferase and chromatin immunoprecipitation experiments. Cell viability was tested by cell counting kit-8 and colony formation assay. The malondialdehyde (MDA), Fe²⁺ content, and lipid reactive oxygen species (ROS) levels were examined by utilizing the corresponding reagent kits. The protein expression of ABCB6, SALL4, GPX4, GCLC, and SLC3A2 were determined via western blot. High expression of ABCB6 was detected in CC. ABCB6 overexpression suppressed ferroptosis and dramatically declined the levels of MDA, lipid ROS, and Fe²⁺ in cells. Furthermore, it induced mitochondrial membrane potential dysfunction and substantially suppressed the fluorescence intensity of GFP-LC3, which in turn promoted the expression of GPX4, GCLC, and SLC3A2 proteins and prevented CC cell ferroptosis. The cell rescue experiment verified that SALL4 initiated ABCB6 activation to mediate mitophagy and prevent ferroptosis in CC cells. The findings evidenced that the SALL4/ABCB6 axis suppresses mitophagy to hinder ferroptosis in CC. The mitophagy pathway may be essential for ABCB6 to regulate ferroptosis in CC.