Targeting proteostasis of the HEV replicase to combat infection in preclinical models

•We identified 17 HSP90 inhibitors via high-throughput screening of anti-HEV compounds using replicon models.•Inhibiting the HEV replicase-HSP90 interaction releases ORF1 for K48-linked ubiquitination and proteasomal degradation.•Cytosolic ORF1-HSP90 aggregates are critical for HEV replication.•Preclinical studies demonstrate that targeting HSP90 prevents sustained HEV infection and liver injury in rodents.