FBXL18 activating AKT/CCND1 signaling pathway mediates radioresistance in esophageal squamous cell carcinoma

F-box and leucine-rich repeat protein 18 (FBXL18) is closely associated with cancer progression. However, its role in regulating the radioresistance of esophageal squamous cell carcinoma (ESCC) remains unclear. Radioresistant ESCC cells were developed using fractional doses of X-ray irradiation, and validated via cell counting kit-8 (CCK-8) assay. The sensitivity of these radioresistant cells to radiotherapy was also assessed using CCK-8. The expression levels of FBXL18 and Cyclin D1 (CCND1) were analyzed through Western blotting. RNA interference (RNAi) technology was employed to investigate whether silencing FBXL18 could reduce ESCC radioresistance and inhibit the AKT/CCND1 signaling pathway. Co-immunoprecipitation and Western blotting were used to evaluate the polyubiquitination of AKT. Radioresistant ESCC cells were successfully established, and FBXL18 expression was significantly elevated in these cells. Increased levels of phosphorylated AKT (p-AKT) and CCND1 were also observed. Silencing FBXL18 notably reduced the radioresistance of ESCC cells and decreased p-AKT and CCND1 expression levels. Also, FBXL18 was found to interact with AKT, promoting its K63-linked polyubiquitination, and activating the AKT/CCND1 signaling pathway. FBXL18 interacts with AKT and facilitates its K63-linked polyubiquitination, thereby activating AKT/CCND1 signaling while maintaining the radioresistance of ESCC cells. [BMB Reports 2026; 59(9): 432-437].