CMKLR1 as a Therapeutic Target: Vitamin D-Mediated Suppression of Inflammation and Oxidative Stress in SA-AKI

Sepsis-associated acute kidney injury (SA-AKI) is a severe complication of sepsis, primarily driven by immune-inflammatory dysregulation and oxidative stress, and 1,25-Dihydroxyvitamin D₃ (1,25(OH)₂D₃) shows renoprotective potential, yet its molecular targets and mechanisms remain unclear. Transcriptomic data of SA-AKI from GEO were analyzed by ssGSEA for immune infiltration, differential expression analysis, WGCNA, and machine learning (LASSO, SVM-RFE, Random Forest) to identify the biomarkers. In vivo, SA-AKI was induced by cecal ligation and puncture (CLP) in mice treated with 1,25(OH)₂D_3, and renal function, histology, inflammatory cytokines, oxidative stress markers, and CMKLR1 expression were evaluated. In vitro, LPS-stimulated HK-2 cells were treated with 1,25(OH)₂D₃ with or without CMKLR1 overexpression to assess cytokines, cell viability, apoptosis, and oxidative stress. Four key biomarkers-CMKLR1, COL1A1, RPS19, and THBS1-were identified by machine learning, with CMKLR1 as the key target. In SA-AKI mice, 1,25(OH)₂D₃ downregulated CMKLR1, improved renal function, and reduced inflammation and oxidative stress. In LPS-stimulated HK-2 cells, it dose-dependently suppressed cytokine release, restored cell viability, and alleviated oxidative stress, while CMKLR1 overexpression partially reversed these effects. CMKLR1 was identified as a key immune inflammation target in SA-AKI. 1,25(OH)₂D₃ was protected against renal injury by suppressing CMKLR1, and mitigating inflammation, oxidative stress, and apoptosis, while CMKLR1 overexpression partially reversed these effects. These findings highlight CMKLR1 as a potential therapeutic target for SA-AKI.