Dapagliflozin Inhibits BK Polyomavirus Replication via AMPK Signaling

BK polyomavirus (BKPyV) infection is a significant contributor of graft loss in kidney transplant recipients, yet no effective antiviral therapy is currently approved. This study investigated whether the SGLT2 inhibitor dapagliflozin could suppress BKPyV replication. BKPyV-infected HK-2 cells were treated with dapagliflozin, and viral load, protein expression, and noncoding control region (NCCR) transcriptional activity were analyzed. siRNA-mediated knockdown of AMPK was used to verify its role in dapagliflozin-mediated response. Dapagliflozin treatment at 10 and 20 μM resulted in a dose-dependent suppression of BKPyV progeny release into the supernatant and a concomitant reduction in large T-antigen (TAg) and VP1 protein expressions. These antiviral effects were achieved without compromising host cell viability, as no significant cytotoxicity was observed at the doses utilized. Luciferase reporter assays revealed that dapagliflozin markedly attenuated TAg-driven NCCR transcriptional activity in both early and late orientations, effectively disrupting viral autoregulation. While high-glucose conditions (25 mM) enhanced BKPyV replication and reduced baseline AMPK phosphorylation, the inhibitory efficacy of dapagliflozin remained consistent. Mechanistically, dapagliflozin increased AMPK phosphorylation even under hyperglycemic stress. The suppression of viral progeny and NCCR activity was significantly reversed upon AMPK knockdown, demonstrating that AMPK activation is required for dapagliflozin-mediated viral suppression regardless of the glucose environment. Dapagliflozin inhibits BKPyV replication through an AMPK-dependent pathway. These results provide a strong rationale for evaluating SGLT2 inhibitors as a novel strategy to reduce the severity of BKPyV infection in transplant recipients.