Dexmedetomidine alleviates sepsis-associated acute kidney injury by inhibiting renal tubular ferroptosis via JNK/MAPK-LCN2 pathway.

backgroundSepsis-associated acute kidney injury (SA-AKI), one of the most common complications of sepsis, significantly prolongs hospitalization, increases mortality, and elevates risks of cardiovascular events and chronic kidney disease. Critically, there are insufficient effective and safe clinical treatment drugs for SA-AKI, and new therapeutic strategies urgently need to be explored. Dexmedetomidine (Dex), a clinically widely used, highly selective α2-adrenoceptor agonist, exhibits sedative, analgesic, anxiolytic, sympatholytic, and opioid-sparing properties. Although recent clinical studies demonstrate its protective effects against SA-AKI, Dex's mechanisms of action remain incompletely understood and require further elucidation.

methodsWe performed RNA sequencing on kidneys from Dex-treated septic mice to analyze differential gene expression and identify key pathways and genes. Comprehensive in vivo and in vitro experiments-including generation of stable LCN2-overexpressing HK-2 cells, transmission electron microscopy, flow cytometry, pharmacological inhibition assays, and western blot analysis-were conducted to elucidate Dex's functions and mechanisms in SA-AKI.

resultsTranscriptome sequencing revealed enrichment of ferroptosis and MAPK pathways, with LCN2 identified as the key gene. Functional experiments demonstrated that Dex alleviates SA-AKI and reduces mortality by inhibiting ferroptosis through improved renal mitochondrial dysfunction, suppressed lipid peroxidation, and attenuated inflammatory responses during sepsis. Mechanistically, Dex suppressed sepsis-induced MAPK pathway activation and reduced LCN2 expression via inhibition of JNK phosphorylation, consequently diminishing ferroptosis and ultimately attenuating SA-AKI.

conclusionsDex mitigates ferroptosis in SA-AKI by counteracting sepsis-induced dysregulation of the JNK/MAPK-LCN2 axis. These findings provide novel mechanistic evidence supporting Dex as a potential therapeutic agent against SA-AKI.