NADPH oxidase activator 1 (NOXA1) suppresses ferroptosis and radiosensitization in colorectal cancer

Radiotherapy is one of the main treatments for colorectal cancer (CRC), but due to the intrinsic resistance of cells or resistance caused by long-term radiotherapy, the effectiveness of this treatment is limited for some CRC patients. Consequently, identifying novel sensitization strategies is essential. This study identifies Noxa1 as a marker linked to radiotherapy resistance in CRC, suggesting its potential as a prognostic biomarker for patients with CRC. The study found that Noxa1 was significantly overexpressed in radiotherapy-resistant colorectal cancer patients, correlating with a poor prognosis. Additionally, we discovered that the high expression of Noxa1 was negatively correlated with ferroptosis and primarily played a role through the glutathione metabolic pathway, as indicated by GSVA analysis. Experimental data indicated that the expression levels of NOXA1, SLC7A11, and GPX4 were significantly elevated in CRC cell lines resistant to radiotherapy. The expression of SLC7A11 and GPX4 decreased after the knockdown of Noxa1, leading to an increase in cellular ROS levels, which induced ferroptosis and sensitized the cells to radiotherapy. Therefore, Noxa1 might influence the radiotherapy sensitivity of CRC via regulating ferroptosis. Targeting Noxa1 could enhance radiotherapy sensitization and improve the prognosis of CRC patients.