TIGAR drives colorectal cancer ferroptosis resistance through ROS/AMPK/SCD1 pathway.

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and major cause of cancer death in the world. Ferroptosis is a recently identified type of regulated cell death. Increasing evidence has shown that ferroptosis plays an important regulatory role in the occurrence and development of cancer. This study identified TIGAR as a potential regulator of ferroptosis resistance in the development of CRC. We showed that TIGAR expression in CRC tissues is significantly higher than that in adjacent normal tissues. Knockdown of TIGAR significantly caused an increase in erastin-induced ferroptosis in SW620 and HCT116 cells. Notably, knockdown of TIGAR significantly decreased GSH/GSSG ratio, increased lipid peroxidation production, and facilitated the accumulation of lipid peroxidation product malondialdehyde (MDA), and rendered CRC cells more sensitive to erastin induced ferroptosis. Furthermore, TIGAR inhibition repressed SCD1 expression in a redox and AMPK-dependent manner. Thus, these results suggest that TIGAR induces ferroptosis resistance in CRC cells via the ROS/AMPK/SCD1 signaling pathway.