Imipramine inhibits feline infectious peritonitis virus infection by targeting host cholesterol metabolism via NPC1

Feline infectious peritonitis (FIP), a fatal disease caused by FIP virus (FIPV), currently lacks effective vaccines and treatments. Imipramine, a tricyclic antidepressant with known broad-spectrum antiviral properties, was investigated for its efficacy against FIPV. Our in vitro studies demonstrated that imipramine inhibits FIPV infection in a dose-dependent manner, with a high selectivity index (SI = 291) and maximal effect when administered during co-treatment. Time-of-addition assays revealed that imipramine acts at multiple stages, interfering with both viral entry and replication. Mechanistically, we found that imipramine targets the host protein Niemann-Pick C1 (NPC1), disrupting cholesterol metabolism to block viral entry. It also independently suppresses FIPV-induced pro-inflammatory cytokine production without relying on type I interferon signaling. Notably, in an in vivo model, imipramine treatment reduced viral loads and alleviated clinical signs in FIPV-infected cats. These findings collectively identify imipramine as a promising, host-targeted therapeutic candidate for FIP.