XDH Inhibits the Progression of Colorectal Cancer via Regulating Ferritinophagy Signaling

Xanthine dehydrogenase (XDH) is involved in the progression of various cancer. This study aimed to investigate its potential in colorectal cancer (CRC). Gene expression was determined using RT‐qPCR, Western blot, immunohistochemistry, and immunofluorescence. Cell behaviors were analyzed using CCK‐8, colony formation, wound healing, transwell migration, TUNEL, PI staining. In vivo assay was conducted to verify the role of XDH in CRC. Histological analysis was performed using HE staining. We found that XDH was downregulated in CRC. XDH overexpression suppressed proliferation and aggressiveness of CRC cells, whereas XDH knockdown exerted opposite effects. XDH selectively increased purine metabolites and promoted impairment of mitochondrial metabolism. Mechanistically, XDH activated NCOA4‐dependent ferritinophagy signaling and drove CRC cells to ferroptosis, which was reversed by 3‐MA. Taken together, XDH inhibits the progression of CRC via mediating ferritinophagy and ferroptosis. Therefore, XDH/ferritinophagy may be a potential target for CRC.