CCDC25 regulates sepsis-associated liver injury via neutrophil extracellular traps

To elucidate the role of coiled-coil domain containing 25 (CCDC25) involvement in sepsis-associated liver injury (SALI) through the regulation of NETs formation, and to assess its protective effects. By constructing CCDC25 −/− and wild-type C57BL/6 mouse SALI models, with or without DNase I intervention, the pathological phenotype of SALI was systematically evaluated. Histological analysis, biochemical detection, Western blot, immunofluorescence and transcriptome sequencing were used to evaluate the liver function, pro-inflammatory cytokines levels, and neutrophil-related proteins across the different treatment groups. CCDC25 deficiency significantly alleviated liver injury, suppressed inflammatory responses, and reduced NETs formation. In comparison with the wild-type control (WC) group, wild-type model (WM) group exhibited higher liver indices, contents of liver enzymes [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)], pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β)], neutrophil extracellular traps (NETs) formation, and myeloperoxidase (MPO) activity. In contrast, all aforementioned indicators in the wild-type DNase I-treatment (WD) group showed a decrease compared with the WM group. Similarly, the above indicators in the CCDC25 −/− model (CM) group were also higher than those in the CCDC25 −/− control (CC) group but lower than those in the WM group. When compared with the CM group, the CCDC25 −/− DNase I-treatment (CD) group showed no obvious changes in the all above-mentioned indicators, except for a significant decrease in the related proteins of NETs in the liver. Additionally, transcriptome sequencing of liver tissues from the WM and CM groups revealed that there were 73 differentially expressed genes (DEGs) enriched in cell metabolism and the PPAR signaling pathway. The deficiency of CCDC25 significantly alleviates SALI by inhibiting the formation of NETs and neutrophil infiltration, reducing the release of pro-inflammatory cytokines, and protecting hepatocytes from damage, potentially via the PPAR signaling pathway. Our work provides a theoretical basis for the development of precise treatment strategies targeting CCDC25.