Deficiency of S100A9 Alleviates Sepsis-Induced Acute Liver Injury through Regulating AKT-AMPK-Dependent Mitochondrial Energy Metabolism

Acute liver injury (ALI) is recognized as a serious complication of sepsis in patients in intensive care units (ICUs). S100A8/A9 is known to promote inflammation and immune responses. However, the role of S100A8/A9 in the regulation of sepsis-induced ALI remains known. Our results indicated that S100A8/A9 expression was significantly upregulated in the livers of septic mice 24 h after cecal ligation and a puncture (CLP) operation. Moreover, S100A9-KO in mice markedly attenuated CLP-induced liver dysfunction and injury, promoting the AMPK/ACC/GLUT4-mediated increases in fatty acid and glucose uptake as well as the improvement in mitochondrial function and ATP production. In contrast, treatment with the AMPK inhibitor Compound C reversed the inhibitory effects of S100A9 KO on CLP-induced liver dysfunction and injury in vivo. Finally, the administration of the S100A9 inhibitor Paquinimod (Paq) to WT mice protected against CLP-induced mortality, liver injury and mitochondrial dysfunction. In summary, our findings demonstrate for the first time that S100A9 plays an important pro-inflammatory role in sepsis-mediated ALI by regulating AKT-AMPK-dependent mitochondrial energy metabolism and highlights that targeting S100A9 may be a promising new approach for the prevention and treatment of sepsis-related liver injury.

Automated summary

Acute liver injury (ALI) is a serious complication of sepsis in ICU patients. S100A8/A9, known for promoting inflammation and immune responses, has been found to play a role in the regulation of sepsis-induced ALI. The study shows that S100A9 deficiency attenuates liver dysfunction and injury in septic mice, while treatment with S100A9 inhibitor protects against sepsis-induced mortality, liver injury, and mitochondrial dysfunction. These findings suggest that targeting S100A9 may be a promising approach for the prevention and treatment of sepsis-related liver injury.