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<p>Sepsis is a clinical syndrome triggered by a dysregulated host response to pathogens that leads to multiple organ dysfunction. Intestinal barrier function plays a pivotal role in the pathogenesis and progression of sepsis. The present study investigated the potential therapeutic role of dexmedetomidine (DEX) in sepsis-induced intestinal injury and explored the underlying molecular mechanisms. This study included a cohort of 57 patients with sepsis treated with or without DEX. A mouse model of cecal ligation and puncture (CLP)-induced sepsis combined with lipopolysaccharide (LPS)-challenged intestinal epithelial cells was used to evaluate the therapeutic potential of DEX against sepsis-associated intestinal injury. Serum levels of inflammatory markers (TNF-α, IL-6) and the intestinal injury biomarker I-FABP were significantly lower in the DEX-treated group (<i>n</i> = 30) compared to the non-DEX group (<i>n</i> = 27) in sepsis patients (<i>P</i> &lt; 0.05). DEX improved survival rates, attenuated intestinal inflammation (TNF-α, IL-6), inhibited epithelial apoptosis, and alleviated sepsis-induced intestinal barrier damage (ZO-1 and claudin-1) in CLP mice. In vitro, treatment with DEX protected against LPS-induced inflammation, apoptosis, and transepithelial electrical resistance (TEER) reduction in Caco-2 cells. Mechanistically, DEX upregulated SIRT3 levels, thereby reducing the expression of phosphorylated JAK2 and STAT3, inhibiting intestinal epithelial apoptosis and enhancing the expression of tight junction proteins (ZO-1, occludin, and claudin-1). Furthermore, the regulatory effects of DEX on intestinal damage disappeared when the SIRT3 antagonist, 3-TYP, was added. SIRT3 knockdown partially abrogated the protective effects of DEX against LPS-induced inflammation, apoptosis, and TEER reduction. These findings provide novel insights into the protective role of DEX against sepsis-induced intestinal injury, at least partially by regulating inhibition of SIRT3/JAK2/STAT3-mediated apoptosis, supporting DEX as a promising therapeutic candidate for the prevention and treatment of sepsis-related intestinal damage.</p>

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Dexmedetomidine regulates the SIRT3-mediated JAK2/STAT3 signaling pathway to protect against sepsis-induced intestinal injury

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月29日

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  • Haodi Gu,
  • Lili Xu,
  • Xinrou Yu,
  • Junjie Xiang,
  • Yue Shan,
  • Gang Ye

摘要

Sepsis is a clinical syndrome triggered by a dysregulated host response to pathogens that leads to multiple organ dysfunction. Intestinal barrier function plays a pivotal role in the pathogenesis and progression of sepsis. The present study investigated the potential therapeutic role of dexmedetomidine (DEX) in sepsis-induced intestinal injury and explored the underlying molecular mechanisms. This study included a cohort of 57 patients with sepsis treated with or without DEX. A mouse model of cecal ligation and puncture (CLP)-induced sepsis combined with lipopolysaccharide (LPS)-challenged intestinal epithelial cells was used to evaluate the therapeutic potential of DEX against sepsis-associated intestinal injury. Serum levels of inflammatory markers (TNF-α, IL-6) and the intestinal injury biomarker I-FABP were significantly lower in the DEX-treated group (n = 30) compared to the non-DEX group (n = 27) in sepsis patients (P < 0.05). DEX improved survival rates, attenuated intestinal inflammation (TNF-α, IL-6), inhibited epithelial apoptosis, and alleviated sepsis-induced intestinal barrier damage (ZO-1 and claudin-1) in CLP mice. In vitro, treatment with DEX protected against LPS-induced inflammation, apoptosis, and transepithelial electrical resistance (TEER) reduction in Caco-2 cells. Mechanistically, DEX upregulated SIRT3 levels, thereby reducing the expression of phosphorylated JAK2 and STAT3, inhibiting intestinal epithelial apoptosis and enhancing the expression of tight junction proteins (ZO-1, occludin, and claudin-1). Furthermore, the regulatory effects of DEX on intestinal damage disappeared when the SIRT3 antagonist, 3-TYP, was added. SIRT3 knockdown partially abrogated the protective effects of DEX against LPS-induced inflammation, apoptosis, and TEER reduction. These findings provide novel insights into the protective role of DEX against sepsis-induced intestinal injury, at least partially by regulating inhibition of SIRT3/JAK2/STAT3-mediated apoptosis, supporting DEX as a promising therapeutic candidate for the prevention and treatment of sepsis-related intestinal damage.