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

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.