Annexin A1 enhances liver repair after acetaminophen-induced liver injury by regulating neutrophils function

Acetaminophen (APAP)-induced acute liver injury (AILI) is a major cause of acute liver failure (ALF), for which effective and timely treatments remain limited. The mechanisms that drive irreversible progression to ALF are not fully understood. Annexin A1 (ANXA1), an anti-inflammatory factor, is implicated in several inflammatory diseases, but its role in APAP-induced liver injury is unclear. In this study, we establish a clinically relevant mouse model of APAP-induced AILI and show that ANXA1 expression increases in the liver, primarily originating from infiltrating neutrophils. ANXA1 deficiency exacerbated liver damage and hindered tissue repair, partly due to the formation of neutrophil extracellular traps (NETs) and altered neutrophil phenotypes. Inhibition of NETs by DNase I restored liver repair and promoted a shift of neutrophils toward an N2 anti-inflammatory phenotype in ANXA1-deficient mice. Furthermore, treatment with Ac2-26, an ANXA1-derived peptide, suppressed NET formation and modulated neutrophil phenotypes to alleviate liver injury. These findings suggest that ANXA1 facilitates liver repair after APAP-induced injury by reprogramming neutrophils via NETs inhibition, offering a promising therapeutic target to enhance recovery from drug-induced liver injury.