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 + Slc11a1 f/f ) significantly alleviated liver injury and improved survival. Mechanistically, SLC11A1 drives intracellular Fe 2 + 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.