Cereblon promotes influenza A virus replication through AMPK ubiquitination.

Influenza A and B viruses (IAV and IBV) continually threaten global health, with IAV posing a risk of emerging pandemics. Rapid viral evolution makes current treatments less effective, highlighting the urgent need for broad-spectrum antivirals. Targeting host factors essential for viral replication may offer a highly promising broad-spectrum antiviral strategy. In this context, cereblon (CRBN), a substrate adaptor of the CRL4 E3 ubiquitin ligase complex, is found to promote both IAV and IBV replication as a key pro-viral host factor. Mechanistically, CRBN targets and degrades AMP-activated protein kinase (AMPK) via the proteasome. This CRBN-driven degradation shifts the metabolism of infected cells toward anabolism, promoting lipid droplet (LD) formation and creating a microenvironment conducive to viral replication. Genetic depletion or inhibition of CRBN stabilizes AMPK, significantly reduces LD formation, and effectively suppresses the replication of various IAV and IBV strains in vivo, demonstrating its broad-spectrum potential. Notably, Crbn knockout mice show marked resistance to lethal IAV infection. CRBN inhibition with immunomodulatory imide drugs, known CRBN inhibitors, significantly decreases IAV replication in vivo. This research underscores CRBN as a crucial regulator of host metabolism during IAV infection, revealing the CRBN-AMPK axis as a promising target for developing host-directed antivirals against IAV.