Targeting MGLL: Terazosin Regulates Glycerolipid Metabolism to Mitigate Endothelial Cell Senescence.

Abstract

Metabolic disorders often arise in senescent endothelial cells, which impair endothelial function, lead to diminished vasodilation, increased vascular stiffness, and ultimately contribute to cardiovascular disease pathogenesis. Despite notable advancements, the molecular mechanisms driving endothelial senescence and its contribution to vascular aging remain incompletely understood, thereby limiting the development of effective therapeutic strategies. Here, we investigated the protective role of terazosin (TZ) against vascular endothelial senescence using both in vivo (aged mice) and in vitro (human umbilical vein endothelial cells, HUVECs) models, combined with senescence-associated β-galactosidase (SA-β-gal) staining, lipidomics, and molecular docking simulations. TZ treatment significantly improved endothelium-dependent vasodilation, reduced vascular stiffness, and attenuated the expression of senescence markers in aged mice. Mechanistically, lipidomics revealed that TZ reduced intracellular palmitic acid (PA) accumulation in senescent endothelial cells. Furthermore, clinical observations confirmed decreased plasma PA levels and improved endothelial function in patients receiving TZ. Monoglyceride lipase (MGLL), which hydrolyzes monoglycerides into PA and glycerol, was markedly upregulated in senescent endothelial cells and aged vascular tissues. TZ directly bound to MGLL and inhibited its enzymatic activity, thereby mitigating PA-driven endothelial senescence. Collectively, these findings identify MGLL as a novel metabolic driver of endothelial senescence and establish TZ as a potential therapeutic agent for age-related vascular diseases.