Identification of an IRF–ZBP1–caspase-8–NINJ1 axis in driving PANoptosis and pathology during alcohol-associated liver disease.

Alcohol-associated liver disease (ALD) is a chronic inflammatory condition in which the innate immune pathways driving liver injury are not fully defined. In this study, we used clinical liver and serum samples, together with mouse models of ALD, to investigate the role of the innate immune sensors in disease pathogenesis. We observed increased ZBP1 expression in patients with ALD, with levels correlated with disease progression. Ethanol exposure induced ZBP1-dependent inflammatory cell death (PANoptosis) in both immune cells (including macrophages, monocytes, and Kupffer cells) and non-immune cells (hepatocytes). Basal ZBP1 expression was upregulated by the interferon regulatory factors IRF1 and IRF9, and ZBP1 activation engaged a PANoptotic pathway, where caspase-8 was a central regulator; the cell death was executed by NINJ1-mediated membrane rupture, independent of gasdermin D, gasdermin E, and MLKL. In ALD mouse models, Zbp1-deficient animals were significantly protected from liver injury and pathology. ZBP1 and NINJ1 expression were also elevated in liver and serum from patients with ALD, supporting their potential as disease biomarkers. Together, these data define an IRF–ZBP1–caspase-8–NINJ1 axis as a key driver of inflammatory cell death in ALD and a potential target for therapeutic intervention.