Apatinib inhibits HTNV by stimulating TFEB-driven lysosome biogenesis to degrade viral protein

Hantaan Orthohantavirus (Hantaan virus, HTNV) infection causes hemorrhagic fever with renal syndrome (HFRS) in humans, posing a significant health threat. Currently, there are no long-lasting protective vaccines or specific antivirals available, creating an urgent need for effective antiviral treatments in the clinical management of HFRS. Given that viruses exploit multiple host factors for their replication, host-oriented inhibitors could offer promising therapeutic options. In our study, we screened a library of 2570 drugs and identified apatinib, a kinase inhibitor, as a potent suppressor of HTNV infection both in vitro and in vivo. Mechanistic studies revealed that apatinib exerts its antiviral effect by targeting transcription factor EB (TFEB). Specifically, apatinib inhibits the PI3K-Akt signaling pathway and reduces mTOR phosphorylation, which in turn downregulates TFEB phosphorylation. This facilitates the nuclear translocation of TFEB and enhances lysosomal function by upregulating the expression of lysosome-associated genes and promoting lysosome biogenesis. Consequently, there is an increase in lysosome-mediated viral nucleocapsid protein degradation. The ability of apatinib to stimulate this lysosome-driven antiviral mechanism presents a potential new therapeutic approach for viral infections and offers valuable insights into virus-host interactions during HTNV replication.