An IRF3-POLR2G axis represses liver FGF21 and metabolic transcriptional programs [CUT&Tag Liver IRF3-2D]

Inflammatory signaling in the liver reshapes numerous transcriptional programs, but the mechanisms by which innate immune pathways actively repress metabolic gene expression remain poorly understood. Here we show that IRF3, a master regulator of innate immunity that is activated during alcohol-associated liver disease, suppresses the hepatokine FGF21 and broader metabolic gene programs through a non-canonical transcriptional mechanism. IRF3 does not directly occupy metabolic gene loci but instead transcriptionally induces POLR2G, a core RNA polymerase II subunit, through promoter-proximal interferon-stimulated response elements. Elevated POLR2G selectively accumulates at metabolic gene promoters, reduces RNA polymerase II recruitment, and represses transcription of fatty acid oxidation and lipid metabolism genes. This regulatory axis operates in vivo, is conserved from yeast to mammals, and is evident in human alcohol-associated liver disease. These findings identify an IRF3-POLR2G axis that repurposes core transcriptional machinery to coordinate a metabolic-to-inflammatory transcriptional switch in the liver.