CHI3L1 mediates radiation resistance in colorectal cancer by inhibiting ferroptosis via the p53/SLC7A11 pathway.

Background: Radiotherapy is a key treatment for colorectal cancer (CRC), particularly rectal cancer; however, many patients are resistant to radiation. While it has been shown that CHI3L1 is associated with CRC progression, its specific function and regulatory mechanisms in radiation resistance remain unclear.

Methods: The levels of CHI3L1 in CRC and normal tissue samples were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. To assess the effects of CHI3L1 on CRC cell proliferative, migratory, and invasive capacities, Cell Counting Kit-8 (CCK-8) and Transwell assays were performed. Radiation resistance in CRC cells with varying CHI3L1 expression levels was evaluated through colony formation assay. Western blot and immunofluorescence analyses were conducted to explore the correlation between CHI3L1 and p53 expression levels. Ferroptosis was assessed by determining reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH) concentrations in cells with different CHI3L1 expression levels, and a xenograft mouse model was used to identify the molecular mechanisms of ferroptosis in vivo.

Results: Significant CHI3L1 upregulated was observed in CRC tissues and was associated with promotion of malignant cell behaviors. The number of colonies in CHI3L1-overexpressing groups was significantly greater than that in the control groups following radiation, indicating increased radiation resistance in the former group. Furthermore, CHI3L1 overexpression was associated with p53 downregulation and elevated p53 ubiquitination. Notably, CHI3L1 inhibited the ferroptosis of CRC cells by suppressing p53 expression through the p53/SLC7A11 signaling pathway.

Conclusions: CHI3L1 overexpression promotes the proliferation, migration, invasion, and radiation resistance of CRC cells. Elevated CHI3L1 expression is associated with increased p53 ubiquitination and SLC7A11 upregulation. CHI3L1 promotes radiation resistance by suppressing ferroptosis in CRC cells through the p53/SLC7A11 axis.