Edaravone attenuates carbonyl-stress-driven ApoA-I carboxymethylation and macrophage cholesterol-handling dysfunction in diabetic atherosclerosis.

Diabetes increases atherosclerotic risk, but how carbonyl stress impairs high-density lipoprotein (HDL) function remains unclear. We investigated a glyoxal-apolipoprotein A-I (ApoA-I) pathway and evaluated edaravone as a carbonyl-stress modulator. In a clinically stratified cohort, plasma protein-bound Nε-(carboxymethyl)lysine (CML) and glyoxal increased progressively across controls, diabetes without coronary artery disease, and diabetes with coronary artery disease. Under short-term exposure, glyoxal generated more ApoA-I-bound CML than other carbonyl species. Site-resolved liquid chromatography-tandem mass spectrometry identified Lys23, Lys107, and Lys195 of mature ApoA-I as glyoxal-responsive CML modification sites; corresponding CML-modified peptides were detected in human plasma. In macrophages, glyoxal exposure in the presence of ApoA-I reduced cholesterol efflux and ABCA1 and ABCG1 expression, increased lipid accumulation, and activated NF-κB- and NLRP3-related pathways. Edaravone attenuated ApoA-I CML formation under glyoxal-containing conditions and partially restored cholesterol efflux and inflammatory balance; a cell-free assay supported cell-independent carbonyl interception. In male streptozotocin-induced diabetic Ldlr-/- mice fed a Western diet for 24 weeks, edaravone during the final 12 weeks was associated with lower atherosclerotic burden and broad remodeling of lesion-associated macrophage, cholesterol-handling, adhesion, inflammatory, and elastic-fiber-related readouts. Single-cell transcriptomics showed coordinated macrophage and endothelial remodeling, attenuated inflammatory signaling, and reorganized lipid-handling pathways. These findings provide site-resolved, multiscale evidence that glyoxal-associated ApoA-I CML modification contributes to impaired macrophage cholesterol handling and inflammatory activation in diabetes-associated atherosclerosis. The edaravone-associated phenotype is consistent with carbonyl interception and broader antioxidant, cytoprotective, and signaling effects, warranting further mechanistic and translational investigation.