Pathogenic Ifit1 + neutrophils driven by IRF7 promote liver injury and represent a therapeutic target in acute liver...

Acute liver failure (ALF) is a life-threatening disease with a high mortality rate and limited treatment options. Neutrophils rapidly infiltrate the injured liver, yet their functional heterogeneity and regulatory mechanisms remain poorly understood. We aimed to identify pathogenic neutrophil subsets in ALF and identify potential therapeutic targets.

Single-cell RNA sequencing of liver tissues from murine ALF revealed the expansion of Ifit1 + neutrophil subset, which was conserved across diverse etiologies. This subset exacerbates liver injury by amplifying inflammatory responses and inducing hepatocyte apoptosis. FGL2 was identified as the principal effector secreted by this subset. Mechanistically, IRF7 acted as an upstream transcriptional regulator of Ifit1 + neutrophil differentiation. Neutrophil-specific Irf7 deficiency reduced Ifit1 + neutrophil expansion, diminished FGL2 production, mitigated liver injury, and improved survival. Liver neutrophil-targeted lipid nanoparticles delivering the IRF7 small-molecule inhibitor HS38 selectively inhibited hepatic neutrophil Irf7, mitigating liver damage. Importantly, the translational relevance of this pathway is underscored by the significant expansion of Ifit1 + neutrophils in ALF patients, where their abundance correlated with disease severity.

These findings delineate an IRF7-Ifit1 + neutrophil-FGL2 axis driving ALF pathogenesis and establish its targeted inhibition as a viable therapeutic strategy.