Abstract / Summary
Abstract Hepatic ischemia-reperfusion injury (HIRI) is characterized by sterile inflammation and innate immune activation, yet the mechanisms linking early inflammatory signals to subsequent macrophage recruitment remain incompletely understood. Here, integrative transcriptomic and proteomic profiling identified S100 calcium-binding protein A9 (S100A9) as a prominent HIRI-associated inflammatory mediator. Pharmacological neutralization of S100A9 and genetic loss of S100a9 attenuated liver injury, proinflammatory cytokine expression, and apoptosis in a mouse model of 70% partial warm HIRI. In AML12 cells subjected to oxygen-glucose deprivation/reoxygenation, recombinant S100A9 further increased apoptosis, and bulk RNA sequencing identified Ccl2 , encoding C-C motif chemokine ligand 2 (CCL2), as a major S100A9-responsive transcript. Consistently, S100a9 deficiency reduced hepatic CCL2 expression and the hepatic accumulation of macrophage-like cells after HIRI, whereas conditioned medium from S100A9-treated injured AML12 cells enhanced RAW264.7 macrophage migration. Serum S100A9 concentrations were significantly higher after partial hepatectomy than before surgery in paired patient samples. Together, these findings identify S100A9 as a functional inflammatory mediator in HIRI and support a potential S100A9–hepatocyte CCL2–macrophage recruitment axis. S100A9 may therefore represent a therapeutic target for ischemia-reperfusion-associated liver injury.