Targeting KAT8 alleviates vascular senescence by modulating the INHBA/TGF-β pathway.

Vascular senescence is a fundamental driver of age-related cardiovascular diseases, yet the epigenetic mechanisms controlling this process remain poorly understood. This study investigated the role and underlying mechanisms of lysine acetyltransferase 8 (KAT8), a key histone acetyltransferase, in maintaining endothelial cell homeostasis and preventing vascular senescence. We found that KAT8 expression is consistently downregulated in human aged vessels, senescent rats and mice, and cellular models of aging. Using CRISPR-Cas9-based loss-of-function and gain-of-function approaches in endothelial cells, C57BL/6J mice, and ApoE(-/-) mice models, we demonstrated that KAT8 deficiency exacerbates aging phenotypes, while its overexpression attenuates vascular senescence. Integrated multi-omics analysis, including miRNA-seq, ATAC-seq, and RNA-seq, revealed that hsa-miR-339-3p is responsible for the age-related downregulation of KAT8. Furthermore, we identified that KAT8 suppresses vascular senescence by regulating the inhibin beta (INHBA)/TGF-β/P15 signaling axis. Our findings establish KAT8 as a critical epigenetic guardian against vascular aging and propose targeting the KAT8/INHBA pathway as a novel therapeutic strategy for age-related vascular diseases.