CXCL10/SLC11A1 Axis Exacerbates Septic Liver Injury by Regulating Neutrophil Extracellular Traps Formation to Drive Macrophage Pro‑Inflammatory Polarization.

Intra-abdominal infection frequently progresses to sepsis, where the liver is an early and commonly injured organ. In a cecal ligation and puncture (CLP) mouse model combined with bulk and single‑cell RNA sequencings, we observed marked neutrophil infiltration in the liver that correlated with injury severity. Sepsis‑associated neutrophils displayed a pro‑inflammatory phenotype and specifically upregulated the divalent metal transporter solute carrier family 11 member 1 (SLC11A1). Conditional knockout of Slc11a1 in neutrophils (Ly6G-Cre+ Slc11a1f/f) significantly alleviated liver injury and improved survival. Mechanistically, SLC11A1 drives intracellular Fe2 + accumulation and reactive oxygen species production via the Fenton reaction, promoting the formation of neutrophil extracellular traps (NETs). Hepatocytes were found to secrete C-X-C motif chemokine ligand 10 (CXCL10) through nuclear factor kappa B (NF‑κB) activation, which both recruit neutrophils and stimulates the JAK/STAT1/SLC11A1 axis, thereby enhancing NETs‑mediated pro‑inflammatory macrophage polarization. Clinically, peripheral blood CXCL10 levels correlated with liver injury markers in sepsis patients. Neutralization of CXCL10 using an anti-CXCL10 antibody or liver-specific knockdown of CXCL10 via Adeno-Associated Virus (AAV) reduced NETs formation and attenuated liver damage in CLP mice. This study delineates a "CXCL10-SLC11A1-NETs" signaling axis that exacerbates sepsis‑induced liver injury, offering a novel target for therapeutic intervention.