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bioRxiv · 10.64898/2026.09.22.753659

Senescence-associated KRAS upregulation in peripheral T cells links to premature coronary artery disease

Sun, Z.·Yang, Z.·Wang, X.·Zhang, M.·Gao, R.·Yang, M.·Li, Y.·Liu, Q.·Hou, J.
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Abstract

Aims: Premature coronary artery disease (PCAD) lacks specific molecular drivers, and the role of immunosenescence is unclear. We investigated whether aging-related gene dysregulation in T cells contributes to PCAD. Methods: We combined bulk transcriptomics of PBMCs from 12 PCAD patients and 21 controls, single-cell RNA sequencing of PBMCs and human atherosclerotic plaques, weighted gene co-expression network analysis, gene perturbation network analysis, and molecular docking. Results: KRAS was identified as a hub gene intersecting PCAD-associated genes and aging-related genes. Single-cell analysis showed KRAS upregulation predominantly in effector CD8+ T cells, which exhibited the highest senescence scores that were further elevated in disease. Network perturbation of KRAS strongly impacted the cell killing pathway. KRAS-high effector CD8+ T cells were detected in coronary and carotid plaques, displaying enhanced cytotoxicity, exhaustion, and senescence features. Additionally, a candidate small molecule was computationally predicted to bind inactive KRAS. Conclusions: Elevated KRAS expression in senescent, cytotoxic CD8+ T cells is associated with PCAD, bridging immunosenescence and premature atherosclerosis. This finding provides a novel biomarker candidate and potential therapeutic entry point, awaiting further functional validation.

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Sun, Z., Yang, Z., Wang, X., Zhang, M., Gao, R., Yang, M., Li, Y., Liu, Q., Hou, J.. 2026-09-28. Senescence-associated KRAS upregulation in peripheral T cells links to premature coronary artery disease. https://doi.org/10.64898/2026.09.22.753659

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