Abstract

Colorectal cancer (CRC) has a high incidence and mortality rate worldwide, with chemotherapy being a cornerstone of treatment for locally advanced CRC patients (LACRC). Despite the relatively high efficacy of chemotherapy regimens like FOLFOX and CAPEOX, the resistance of chemotherapy remains a significant challenge. In this study, we identified sperm associated antigen 5 (SPAG5) as a potential therapeutic target in LACRC patients. High SPAG5 expression was correlated with improved progression-free survival (PFS) and overall survival (OS) in CRC patients receiving chemotherapy, as demonstrated by analyses of multiple cohorts, including TCGA, GEO and FUSCC. Mechanistically, SPAG5 overexpression promoted ferroptosis in CRC cells, enhancing chemotherapy efficacy through increased reactive oxygen species (ROS). SPAG5 depletion reduced ROS levels, attenuated ferroptosis, and decreased the cytotoxic effects of chemotherapy. These results indicate that SPAG5 can modulate ROS-dependent ferroptosis to enhance the chemotherapeutic response. Furthermore, inhibition of ROS reversed the chemotherapy-sensitizing effect mediated by SPAG5. Together, these findings suggest that SPAG5 may serve as a promising biomarker and therapeutic target to potentiate the cytotoxic effects of chemotherapy in LACRC patients.