Interferon Regulatory Factors in Alcohol-Associated Liver Disease: Cell-Type Programs, Danger Signaling, and...

Alcohol-associated liver disease (ALD) contributes substantially to the global burden of cirrhosis and liver-related mortality, driven by ethanol metabolism, oxidative stress, and dysregulated immune signaling. Despite rapidly growing evidence implicating interferon regulatory factors (IRFs) in ALD pathogenesis, an integrated framework linking ethanol-induced danger signals to cell-type-specific IRF programs is lacking. In this comprehensive review, we summarize current knowledge on IRF-centered signaling networks in ALD, spanning DAMP-PAMP sensing, post-translational IRF regulation, and downstream inflammatory, metabolic, and fibrogenic outcomes across various cell types in the liver, including hepatocytes and immune-related cells such as Kupffer cells, monocyte-derived macrophages, dendritic cells, T cells, hepatic stellate cells (HSC), and neutrophils. We also focus on how ethanol-driven DAMP and PAMP signals activate TLR4, TLR9, and cGAS-STING pathways to engage a coordinated network of IRFs-including IRF1, IRF3, IRF4, IRF5, IRF7, and IRF9-that collectively shape inflammatory, metabolic, and cell-fate programs across hepatic cell populations. We further highlight emerging therapeutic strategies such as STING/TBK1 inhibition, NETosis blockade, IL-22-based epithelial repair, and JAK-STAT modulation that converge on IRF pathways. In summary, this review outlines how IRFs contribute to ALD pathogenesis and discusses the potential implications for the development of targeted therapies.