FASN promotes Hantavirus infection by controlling fatty acid synthesis derived from the tree shrew infection model

Hantaan virus (HTNV) is the principal etiological agent of hemorrhagic fever with renal syndrome (HFRS) in Asia. To date, however, progress in defining mechanisms of host-pathogen interaction has been limited by the absence of an appropriate animal model. In the present study, the tree shrew (Tupaia belangeri) was shown to be permissive to HTNV infection and to recapitulate key renal pathology and immunological features observed in patients with HFRS. Following intranasal challenge, viral replication occurred predominantly in the kidney, spleen, and lung, accompanied by tubular dilation, glomerular congestion, and interstitial inflammation. Transcriptomic profiling further demonstrated that HTNV infection induced metabolic reprogramming to enhance fatty acid oxidation and suppress de novo lipogenesis. At the same time, fatty acid synthase (FASN), a key enzyme in lipid biosynthesis, proved to be indispensable for efficient viral replication. Notably, both FASN knockdown and pharmacological inhibition with TVB-3664 markedly suppressed HTNV proliferation through disruption of lipid droplet formation and subsequent amplification of type I interferon responses. Mechanistically, the HTNV nucleocapsid protein (NP) recruited and interacted with FASN, thereby modulating lipogenic activity and suggesting that HTNV exploits fatty acid metabolic pathways to support viral replication through NP-FASN interaction. Collectively, these findings establish a previously unrecognized link between HTNV replication and host lipid metabolic remodeling, identify FASN as a critical host determinant during infection, and highlight the FASN-dependent lipogenic pathway as a promising therapeutic target for HFRS.