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Abstract <p>Vascular leakage in sepsis is critical factors in improving the prognosis of septic patients, with limited treatment options targeting underlying molecular mechanisms. Necroptosis is a form of cell death centered around the RIPK1/RIPK3/MLKL pathway, combining both programmed and inflammatory characteristics. However, its role and mechanism in sepsis-induced vascular leakage remain unclear. In vivo and in vitro, CLP and LPS were used to simulate sepsis model. It was found that the expression levels of RIPK1/RIPK3/p-MLKL in septic VECs were significantly increased, and necroptosis inhibitors significantly improved septic vascular leakage. Transcriptomic and Western blot results suggested that TNFRSF21 plays a key role in necroptosis. shTNFRSF21 inhibited the formation of necrosome (RIPK3/p-MLKL) in septic VECs, improved vascular leakage in septic rats, and prolonged their survival time. The compound Phen-DC3 of inhibiting TNFRSF21 and the anesthetic remimazolam, both downregulated TNFRSF21, thereby improving septic vascular leakage. Our results suggest that TNFRSF21-regulated necroptosis plays an important role in septic vascular leakage, and targeting TNFRSF21 inhibition may be a potential therapeutic strategy for septic vascular leakage.</p> Key messages <p><UnorderedList Mark="Bullet"> <ItemContent> <p>Necroptosis plays a crucial role in sepsis-induced vascular leakage.</p> </ItemContent> <ItemContent> <p>TNFRSF21 promotes necrosome formation by upregulating RIPK3/p-MLKL, leading to endothelial cell death and disruption of the vascular barrier.</p> </ItemContent> <ItemContent> <p>The TNFRSF21 inhibitor Phen-DC3 was identified as a compound that improves sepsis-induced vascular leakage, providing a potential new therapeutic strategy for sepsis treatment.</p> </ItemContent> <ItemContent> <p>The anesthetic remimazolam inhibits TNFRSF21, improving sepsis-induced vascular leakage, offering experimental evidence for the repurposing of existing drugs like remimazolam in the treatment of sepsis.</p> </ItemContent> </UnorderedList></p>

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The role and mechanism of TNFRSF21 in promoting necroptosis of vascular endothelial cells and inducing vascular leakage in sepsis

  • 期刊论文

  • 发表日期：

    2026年4月23日

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  • Juntao Wang,
  • Bindan Zhang,
  • Yujia Wu,
  • Weichao Li,
  • Yuxi Zhang,
  • Daiqin Bao,
  • Haoyu Pei,
  • Caifeng Shi,
  • Han She,
  • Xiaoyan Wang,
  • Qingxiang Mao,
  • Cong Yu

摘要

Abstract

Vascular leakage in sepsis is critical factors in improving the prognosis of septic patients, with limited treatment options targeting underlying molecular mechanisms. Necroptosis is a form of cell death centered around the RIPK1/RIPK3/MLKL pathway, combining both programmed and inflammatory characteristics. However, its role and mechanism in sepsis-induced vascular leakage remain unclear. In vivo and in vitro, CLP and LPS were used to simulate sepsis model. It was found that the expression levels of RIPK1/RIPK3/p-MLKL in septic VECs were significantly increased, and necroptosis inhibitors significantly improved septic vascular leakage. Transcriptomic and Western blot results suggested that TNFRSF21 plays a key role in necroptosis. shTNFRSF21 inhibited the formation of necrosome (RIPK3/p-MLKL) in septic VECs, improved vascular leakage in septic rats, and prolonged their survival time. The compound Phen-DC3 of inhibiting TNFRSF21 and the anesthetic remimazolam, both downregulated TNFRSF21, thereby improving septic vascular leakage. Our results suggest that TNFRSF21-regulated necroptosis plays an important role in septic vascular leakage, and targeting TNFRSF21 inhibition may be a potential therapeutic strategy for septic vascular leakage.

Key messages

Necroptosis plays a crucial role in sepsis-induced vascular leakage.

TNFRSF21 promotes necrosome formation by upregulating RIPK3/p-MLKL, leading to endothelial cell death and disruption of the vascular barrier.

The TNFRSF21 inhibitor Phen-DC3 was identified as a compound that improves sepsis-induced vascular leakage, providing a potential new therapeutic strategy for sepsis treatment.

The anesthetic remimazolam inhibits TNFRSF21, improving sepsis-induced vascular leakage, offering experimental evidence for the repurposing of existing drugs like remimazolam in the treatment of sepsis.