N-Homocysteinylation of HMGB1/2 Promotes Corpus Cavernosum Endothelial Senescence in Erectile Dysfunction.

ABSTRACT: Homocysteine (Hcy) is an age-related risk factor for erectile dysfunction (ED), with enhanced vascular toxicity in middle-aged and elderly individuals. However, folate-based Hcy-lowering therapies have shown limited efficacy, necessitating a reevaluation of its age-dependent pathogenic mechanism. Here, we demonstrate that senescent endothelial cells exhibit heightened responsiveness of methionyl-tRNA synthetase 1 (MARS1) to Hcy, promoting the production of homocysteine thiolactone (HTL) and widespread N-homocysteinylation (K-Hcy) of proteins. K-Hcy, rather than acetylation, drives cytoplasmic translocation and extracellular release of high mobility group box proteins 1 and 2 (HMGB1/2), amplifying the senescence-associated secretory phenotype (SASP). Competitive inhibition of MARS1 with N-a

SUBMITTER: Hu P 

PROVIDER: S-EPMC12631104 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature