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.