High xCT expression indicates poor prognosis and chemoradiotherapy resistance in rectal cancer patients

xCT/SLC7A11, an amino acid transporter, is implicated in various cancers. However, its role in rectal cancer remains unclear. This study aimed to explore its predictive value for prognosis and chemoradiotherapy response in rectal cancer patients. xCT expression was assessed using immunohistochemistry and RT-qPCR, and its associations with clinicopathological features and prognosis were analyzed. Single-cell RNA sequencing data and the TIMER platform were used to examine xCT’s correlation with immune cell infiltration. A prognostic nomogram model was developed and evaluated with ROC, calibration, and decision curve analysis. Cell proliferation and cytotoxicity assays were conducted to assess xCT’s role in ferroptosis and chemoradiotherapy sensitivity. xCT expression was elevated in rectal cancer tissues and correlated with adverse clinicopathological features, including tumor regression grade ( P < 0.001). Single-cell and immune infiltration analyses indicated that xCT was associated with the immune microenvironment. High xCT expression predicted worse overall and disease-free survival, and multivariate analysis confirmed it as an independent prognostic factor. The xCT-based nomogram accurately predicted 1- and 3-year survival rates. Additionally, xCT knockout inhibited cell proliferation and enhanced chemoradiotherapy sensitivity in vitro and in vivo by promoting ferroptosis. High expression of xCT was associated with poor prognosis and chemoradiotherapy response in rectal cancer, representing a potential prognostic marker and therapeutic target.