Hepatic IκBζ promotes alcohol-associated liver disease and acute hepatitis by enhancing CXCL1-Mediated neutrophil infiltration.

Neutrophil infiltration is a critical driver of liver injury; however, the factors regulating neutrophil recruitment remain incompletely understood. IκBζ, encoded by Nfkbiz, is a key transcriptional factor known to influence the inflammatory response. This study aims to investigate whether IκBζ contributes to liver injury and how it affects neutrophil infiltration. Liver-specific Nfkbiz knockout mice (Nfkbiz△Hep) and control mice (Nfkbizf/f) were generated and subjected to various liver disease models. RNA sequencing and chromatin immunoprecipitation (ChIP) assays were used to identify molecular targets of IκBζ. We found that Nfkbiz mRNA levels were significantly elevated in the livers of patients with severe alcohol-associated hepatitis and in mouse models of alcohol-associated liver disease (ALD). This elevation correlated with alanine aminotransferase (ALT) levels. Notably, hepatocyte-specific Nfkbiz deficiency reduced neutrophil infiltration and mitigated liver injury and inflammation following Gao-binge alcohol feeding. Transcriptomic and ChIP assays identified chemokine (C-X-C motif) ligand 1 (Cxcl1) as a direct downstream target of IκBζ. Furthermore, Nfkbiz△Hep mice were also more resistant to concanavalin A (ConA)-induced hepatitis but not acetaminophen or carbon tetrachloride-induced acute liver injury, showing decreased neutrophil infiltration and reduced CXCL1 expression. Finally, therapeutic inhibition of IκBζ using GalNac-siNfkbiz injection alleviated ALD-related liver injury and inflammation, suggesting its potential as a novel therapeutic approach for ALD and other liver diseases characterized by neutrophilic inflammation. Hepatic IκBζ promotes neutrophil infiltration by modulating CXCL1 expression, thereby exacerbating ALD and acute hepatitis. Targeting IκBζ in the liver may provide a novel therapeutic strategy for treating neutrophil-driven liver injuries.