Lung-specific CRBN knockout attenuates influenza a virus-induced acute lung injury in mice: a potential therapeutic approach.

Abstract

Influenza-related acute lung injury is a life-threatening condition primarily caused by uncontrolled replication of the influenza virus and intense proinflammatory responses. Cereblon (CRBN) is a protein known for its role in the ubiquitin-proteasome system and as a target of the drug thalidomide. However, the function of CRBN in influenza virus infection remains poorly understood. In this study, we investigated the impact of CRBN on A/Puerto Rico/8/34 (PR8) influenza virus-induced lung injury and its potential as a therapeutic target. Knocking down CRBN in vitro significantly reduces PR8-induced cell death. Using Sftpc-Cre; Crbn^flox/flox lung-specific Crbn knockout mice, we demonstrated that Crbn deficiency significantly decreased mortality, weight loss, lung pathology, edema, and viral load in PR8-infected mice. PR8-infected Sftpc-Cre; Crbn^flox/flox mice exhibited a marked reduction in lung inflammatory cell infiltration and suppression of MAPK pathway activation, highlighted by a significant downregulation of the MKK4-JNK-c-JUN signaling cascade. Collectively, these findings indicate that CRBN plays a pivotal role in the pathogenesis of influenza-induced lung injury by modulating MAPK pathway signaling, underscoring its therapeutic potential as a target for intervention.