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Background <p>Sepsis-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.</p> Methods <p>We 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.</p> Results <p>Transcriptome 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.</p> Conclusions <p>Dex 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月26日

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  • Boyang Liu,
  • Shengxiang Ao,
  • Li Luo,
  • Lin Qiao,
  • Tianyin Kuang,
  • Hongyan Xiao,
  • Jing Zhou,
  • Shuangqin Yin,
  • Huaping Liang,
  • Fen Li,
  • Weihong Dai,
  • Junyu Zhu

摘要

Background

Sepsis-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.

Methods

We 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.

Results

Transcriptome 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.

Conclusions

Dex 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.