Tedizolid Targets AQP9-JAK/STAT Axis to Suppress Metastatic Progression in Clear Cell Renal Cell Carcinoma: Mechanism and Therapeutic Implications

Metastasis is a primary driver of poor outcomes in clear cell renal cell carcinoma (ccRCC), yet the role of Aquaporin-9 (AQP9) in this process remains unclear. This study aimed to investigate the function, clinical significance, and therapeutic potential of AQP9 in ccRCC. AQP9 expression was analyzed using TCGA data and validated in human tissues and cell lines via Western blot. Functional assays assessed malignant behaviors, while bioinformatics and rescue experiments explored the involvement of the JAK/STAT pathway and epithelial-mesenchymal transition (EMT). Virtual screening, molecular docking, and cellular thermal shift assays (CETSAs) were employed to identify Tedizolid as a potential AQP9 inhibitor, followed by functional validation in vitro and in a xenograft model. AQP9 was significantly upregulated in ccRCC and associated with poor prognosis. The knockdown of AQP9 suppressed proliferation, migration, invasion, and EMT, whereas its overexpression promoted these effects by activating the JAK/STAT pathway. Tedizolid bound directly to AQP9, inhibited cell viability, reversed AQP9-induced malignant phenotypes, and suppressed JAK/STAT signaling both in vitro and in vivo. In conclusion, AQP9 promotes ccRCC metastasis through the JAK/STAT-EMT axis and represents a potential prognostic biomarker and therapeutic target. Tedizolid, identified as a novel AQP9 inhibitor, offers a promising repurposed strategy for ccRCC treatment.