Inverse agonist of ERRγ controls influenza A virus and SARS-CoV-2 infections by targeting SREBP-1c-mediated fatty acid biosynthesis

The periodic emergence of pandemic RNA viral infections, such as COVID-19 and pandemic flus, and the declining efficacy of virus-targeting drugs underscore the need for innovative therapies. Here, we identify the nuclear receptor estrogen-related receptor gamma (ERRγ) as a key regulator of RNA virus replication through its role in reprogramming host fatty acid (FA) biosynthesis. Notably, heterozygous ERRγ knockout reduced influenza A virus (IAV) lung replication, thereby increasing the survival rate. Transactivation of ERRγ in the IAV- or SARS-CoV-2-infected cells was induced by the JNK/c-Jun signaling pathway. DN200434, an ERRγ-specific inverse agonist, showed broad-spectrum antiviral effects by inhibiting the sterol regulatory element-binding protein-1c (SREBP-1c)-dependent fatty acid biosynthesis, which is crucial for virus replication. The administration with DN200434 protected lethal IAV- or SARS-CoV-2-challenged animals. These findings identify ERRγ as a new proviral host factor, highlighting that targeting ERRγ to modulate SREPB-1c-dependent lipidomic reprogramming may represent a promising broad-spectrum antiviral strategy.