Dasatinib alleviates inflammation in sepsis by inhibiting T cell senescence via MAPK14 /NF-κB axis

The pathological progression of sepsis is closely associated with T cell senescence. However, the key signaling pathways regulating this process and potential therapeutic drug remain unclear.

GEO datasets and KEGG enrichment analysis were integrated to screen sepsis-related signaling pathways. Aging-related genes in sepsis were combined with the DSigDB database to predict a potential therapeutic drug. LPS-stimulated Jurkat cells and a CLP-induced mouse model of sepsis were used to evaluate CD4⁺ T cell senescence levels and the interventional effects of Dasatinib, as well as to explore its molecular mechanism. Serum markers of liver and kidney function and histopathological changes were also examined to assess the protective effects of dasatinib against sepsis-induced multiple organ injury.

Both in vitro and in vivo experiments confirmed that sepsis induces CD4⁺ T cell senescence, as evidenced by upregulation of senescence markers and increased release of senescence-associated secretory phenotype (SASP) factors. Intervention with dasatinib significantly reversed this senescent phenotype. Mechanistic studies showed that dasatinib exerts its anti-senescence effects by inhibiting the activation of the MAPK14/NF-κB axis. In the CLP-induced septic mouse model, dasatinib treatment also significantly alleviated multiple organ injury.

Dasatinib alleviates sepsis-induced CD4⁺ T cell senescence and subsequently reduces multiple organ injury by inhibiting the MAPK14/NF-κB signaling pathway, providing a new potential strategy for immunomodulatory therapy of sepsis.