PURPOSE: Acute radiation-induced esophagitis (ARIE) is a common and dose-limiting adverse reaction associated with radiotherapy for thoracic tumors. mRNA sequencing identified CXCR4 as a potential target for noninvasive imaging of ARIE and significant up-regulation of CXCR4 expression was further confirmed in ARIE experimental animal model and clinical samples. This research investigated the feasibility of targeting CXCR4 for the diagnosis and treatment of ARIE. METHODS: ARIE models were established, and magnetic resonance imaging was performed. Dynamic, blocking, histopathological studies, mRNA-sequencing and flow cytometry were conducted. The feasibility of an RESULTS: Increased signal intensity in the esophagus and surrounding tissues was observed in ARIE models, with clinical manifestations confirmed by H&E staining. Immunofluorescence staining demonstrated significant CXCR4 up-regulation. Significantly increased [ CONCLUSION: CXCR4-targeted PET/CT facilitates noninvasive detection of ARIE in experimental animal models. CXCR4 blockade mitigates ARIE, highlighting CXCR4 as a promising theranostic target of ARIE.