A CEBPB-IPO4-FASN-MAVS axis limits innate immune activation and viral pneumonia.

Dysregulation of innate immunity during respiratory RNA virus infections drives systemic hyperinflammation and lung injury. Here, we show that importin β4 (IPO4) has a role in inhibiting antiviral innate immunity. Transcriptomics analysis illustrated a downregulation of IPO4 in alveolar macrophages, lung ciliated epithelium, and peripheral blood mononuclear cells from severely ill patients with COVID-19 or influenza. We further identified CCAAT/enhancer-binding protein beta (CEBPB) as the transcription factor for IPO4 reduction during RNA viral infections. Loss-of-function validation demonstrated that IPO4 dampens the innate antiviral and inflammatory responses in vitro and in vivo. Mechanistically, IPO4 sequesters fatty acid synthase (FASN) to block palmitic acid production, thereby inhibiting mitochondrial antiviral signaling protein (MAVS) activation and the downstream innate immune signaling. Moreover, Adeno-associated virus (AAV)-mediated pulmonary restoration of IPO4 significantly alleviated viral pneumonia in mice. These results indicate that the CEBPB-IPO4-FASN-MAVS axis preserves innate immune homeostasis to avoid inflammatory pathology, highlighting IPO4 as a potential therapeutic target for severe viral pneumonia.