Abstract: Objective: To investigate the protective effect of the phospholipase D2 inhibitor CAY10594 on acute kidney injury (AKI) and its underlying mechanisms. Methodology: Transcriptional profiling (RNA-seq) was performed on the human acute monocytic leukemia cell line THP-1 treated with lipopolysaccharide (LPS) to identify differentially expressed genes. Potential drug molecules were predicted by integrating the Connectivity Map (CMap) database, and CAY10594 was selected as a candidate intervention. Two AKI models were established: LPS-induced sepsis-related AKI and renal ischemia-reperfusion injury (IRI)-induced AKI in C57BL/6 mice. The effect of CAY10594 was assessed by immunofluorescence, Western blot, and ELISA. Results: Both the LPS and IRI models showed elevated levels of inflammatory cytokines, liver and kidney dysfunction, and renal tubular damage. Treatment with CAY10594 significantly reduced serum inflammatory cytokine levels and improved liver and kidney function markers (ALT, AST, CREA, and UREA, P<0.05). Histopathological examination showed that CAY10594 intervention significantly alleviated tubular necrosis and macrophage infiltration, accompanied by reduced F4/80+ macrophage infiltration and downregulation of NLRP3 and KIM-1 expression in the kidneys. Western blot analysis confirmed that CAY10594 inhibited NF-κB pathway activation, reduced NLRP3 expression, and lowered KIM-1 protein levels. Conclusion: CAY10594 improves acute kidney injury by inhibiting inflammation and inflammatory cell infiltration. Its potential mechanism involves suppression of the F4/80-NF-κB-NLRP3 axis to reduce macrophage-mediated inflammatory responses, suggesting potential clinical applicability.

Key words: font-family:Inter, -apple-system, BlinkMacSystemFont, ", font-size:16px, background-color:#FFFFFF, ">acute kidney injury, CAY10594, NLR family pyrin domain containing 3, macrophage