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Background <p>Despite significant advances in acute ischemic stroke (AIS) reperfusion therapies, blood-brain barrier (BBB) dysfunction continues to drive poor clinical outcomes. While endogenous vascular protective mechanisms remain incompletely characterized, kallikrein-related peptidase 10 (KLK10) - a serine protease with unexplored neurovascular functions - represents a promising candidate for BBB regulation.</p> Methods <p>We employed a translational strategy to characterize KLK10 expression in plasma samples from 182 AIS patients, human postmortem stroke brain tissues, and a mouse model of middle cerebral artery occlusion (MCAO). We elucidated KLK10’s functional mechanisms through studies using genetic knockout mice, endothelial-specific KLK10 knockdown models, recombinant KLK10 (rKLK10) administration, KLK10 overexpression in cultured brain endothelial cells (BECs), pharmacological inhibition, and primary BEC cultures.</p> Results <p>We demonstrate that KLK10 is markedly upregulated in both human postmortem stroke brain tissues and MCAO mouse brains, with predominant expression in cerebrovascular endothelial cells. Clinically, plasma KLK10 levels in AIS patients correlate with both disease severity and 3-month prognosis. Functional studies reveal that KLK10 protects against brain injury and BBB disruption by suppressing endothelial inflammatory cell adhesion molecules, and preserving junctional integrity. Mechanistically, KLK10 may exert its protective effects by limiting the cerebrovascular endothelial cyclic GMP-AMP synthase - stimulator of interferon genes - nuclear factor kappa B (cGAS-STING-NF-κB) pathway, a previously unrecognized regulatory mechanism in stroke-associated endothelial dysfunction.</p> Conclusions <p>Our study suggests that KLK10 may serve as a candidate prognostic indicator and potential therapeutic target for AIS, exerting its protective effects via maintaining BBB integrity and via the novel regulation of the cerebrovascular cGAS-STING-NF-κB pathway, thereby offering new insights for vascular protection in stroke and related neuroinflammatory conditions.</p> Graphical Abstract <p></p>

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Endothelial KLK10 maintains blood-brain barrier integrity and mitigates ischemic stroke by limiting the cGAS-STING pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月30日

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  • Xiaoyu Wu,
  • Kegui Zhou,
  • Cong Wang,
  • Yi Zhang,
  • Jiamin Chen,
  • Richard Milner,
  • Jiapei Dai,
  • Longxuan Li

摘要

Background

Despite significant advances in acute ischemic stroke (AIS) reperfusion therapies, blood-brain barrier (BBB) dysfunction continues to drive poor clinical outcomes. While endogenous vascular protective mechanisms remain incompletely characterized, kallikrein-related peptidase 10 (KLK10) - a serine protease with unexplored neurovascular functions - represents a promising candidate for BBB regulation.

Methods

We employed a translational strategy to characterize KLK10 expression in plasma samples from 182 AIS patients, human postmortem stroke brain tissues, and a mouse model of middle cerebral artery occlusion (MCAO). We elucidated KLK10’s functional mechanisms through studies using genetic knockout mice, endothelial-specific KLK10 knockdown models, recombinant KLK10 (rKLK10) administration, KLK10 overexpression in cultured brain endothelial cells (BECs), pharmacological inhibition, and primary BEC cultures.

Results

We demonstrate that KLK10 is markedly upregulated in both human postmortem stroke brain tissues and MCAO mouse brains, with predominant expression in cerebrovascular endothelial cells. Clinically, plasma KLK10 levels in AIS patients correlate with both disease severity and 3-month prognosis. Functional studies reveal that KLK10 protects against brain injury and BBB disruption by suppressing endothelial inflammatory cell adhesion molecules, and preserving junctional integrity. Mechanistically, KLK10 may exert its protective effects by limiting the cerebrovascular endothelial cyclic GMP-AMP synthase - stimulator of interferon genes - nuclear factor kappa B (cGAS-STING-NF-κB) pathway, a previously unrecognized regulatory mechanism in stroke-associated endothelial dysfunction.

Conclusions

Our study suggests that KLK10 may serve as a candidate prognostic indicator and potential therapeutic target for AIS, exerting its protective effects via maintaining BBB integrity and via the novel regulation of the cerebrovascular cGAS-STING-NF-κB pathway, thereby offering new insights for vascular protection in stroke and related neuroinflammatory conditions.

Graphical Abstract