The anti-aging drug Senolytics alleviates vascular endothelial cell senescence by antagonizing the JPX-BRD4-p65 complex

Dec 25, 2025Cellular signalling

The anti-aging drug Senolytics reduces blood vessel cell aging by blocking the JPX-BRD4-p65 protein complex

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

Senolytics (dasatinib + quercetin) alleviated endothelial senescence in human umbilical vein endothelial cells (HUVECs) by suppressing the long non-coding RNA JPX.

Senescence of vascular endothelial cells is crucial in vascular aging.
JPX is involved in promoting senescence in endothelial cells.
Knocking down JPX reduced endothelial cell senescence, while overexpressing it increased senescence.
JPX interacts with specific proteins to enhance the expression of factors associated with senescence.
Senolytics disrupted the JPX-related complex and mitigated senescence in endothelial cells.

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Senescence of vascular endothelial cells (ECs) and smooth muscle cells is pivotal in vascular aging. While the long non-coding RNA JPX has been shown to induce smooth muscle cell senescence, its role in EC senescence remains unknown. Senolytics (dasatinib + quercetin, D + Q) can eliminate senescent cells and attenuate the senescence-associated secretory phenotype (SASP), but their mechanisms in ECs are unclear. Here, we investigated the interplay between Senolytics and JPX in human umbilical vein endothelial cells (HUVECs). Using a lipopolysaccharide (LPS)-induced senescence model, we found that Senolytics alleviated endothelial senescence while suppressing the upregulation of JPX observed in senescent HUVECs. Functional assays showed that JPX knockdown inhibited, whereas JPX overexpression aggravated, EC senescence. Mechanistically, JPX interacted with bromodomain-containing protein 4 (BRD4) and transcription factor p65 to form a JPX-BRD4-p65 complex that promoted SASP expression. In vivo, Senolytics disrupted this complex and effectively mitigated endothelial senescence. Collectively, our study identifies JPX as a key regulator of vascular endothelial senescence and reveals that Senolytics exert anti-senescent effects by antagonizing the JPX-BRD4-p65 complex, providing novel mechanistic insights and potential therapeutic targets for vascular aging-related diseases.

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The anti-aging drug Senolytics alleviates vascular endothelial cell senescence by antagonizing the JPX-BRD4-p65 complex

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