Pathology, research and practice · 2026
Dimethylglycine accelerate atherosclerosis by mediating macrophages ferroptosis via NRF2 pathway suppression.
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Zhang Ruixue, Gu Qishuo, Qu Sheng, Chen Yuwu, Lu Chengbo, Zhao Guangyang, Zhao Weiqing, Chen Weida, Liu Yu, Zhou Xin, Dong Tianwei, Yang Guangyuan
Аннотация
BACKGROUND: Dimethylglycine (DMG) has been shown to be highly correlated with coronary heart disease (CHD), whose pathological basic is atherosclerosis (AS). Macrophage ferroptosis is the crucial pathological events in AS progression, but the underlying mechanism is unclear. Hence, we conducted a series of studies to elucidate the specific effects and mechanism of DMG on macrophages in the progression of AS.
METHOD: A case-control study was conducted on patients with CHD to evaluate the levels of DMG. Additionally, a prospective cohort study was performed to assess the association between baseline serum DMG levels and the incidence of major adverse cardiovascular events (MACE). Single-cell RNA sequencing (scRNA-seq) and proteomics analyses were conducted on the aortas of high-fat diet-fed ApoE knockout (ApoEKO) mice administered with or without DMG. THP-1 were exposed to DMG in vitro to investigate potential underlying mechanisms.
RESULTS: High level DMG level was associated with higher MACE rate in patients with ST-segment elevation myocardial infarction (STEMI). DMG administration significantly decreased the glutathione Peroxidase 4 (GPX4)/solute carrier family 7 member 11 (xCT) expression of macrophages of aortas in ApoEKO mice. Mechanically, Mechanistically, DMG bound to the Ile559 (I559) site of NRF2 (identified by molecular docking and validated by site-directed mutagenesis), inhibited NRF2 nuclear translocation and its promoter enrichment on GPX4/xCT, which was reversed by TBHQ. and mutation of the I559 site (I559S) significantly inhibited the DMG-induced ferroptosis of macrophages. In vivo study demonstrated that the administration of DMG via gavage markedly exacerbated atherosclerotic lesion severity, exhibiting elevated the extent of aortic lipid peroxidation, and increased ferroptosis levels in macrophages, which were ameliorated by TBHQ administration.
CONCLUSIONS: DMG inhibits NRF2 nuclear translocation mainly by binding to the I559 site of NRF2 (identified by molecular docking and validated by site-directed mutagenesis), thereby reducing GPX4/xCT expression and promoting macrophage ferroptosis to accelerate AS. Targeting macrophages ferroptosis may serve as a potential intervention strategy for CHD patients with high DMG.
METHOD: A case-control study was conducted on patients with CHD to evaluate the levels of DMG. Additionally, a prospective cohort study was performed to assess the association between baseline serum DMG levels and the incidence of major adverse cardiovascular events (MACE). Single-cell RNA sequencing (scRNA-seq) and proteomics analyses were conducted on the aortas of high-fat diet-fed ApoE knockout (ApoEKO) mice administered with or without DMG. THP-1 were exposed to DMG in vitro to investigate potential underlying mechanisms.
RESULTS: High level DMG level was associated with higher MACE rate in patients with ST-segment elevation myocardial infarction (STEMI). DMG administration significantly decreased the glutathione Peroxidase 4 (GPX4)/solute carrier family 7 member 11 (xCT) expression of macrophages of aortas in ApoEKO mice. Mechanically, Mechanistically, DMG bound to the Ile559 (I559) site of NRF2 (identified by molecular docking and validated by site-directed mutagenesis), inhibited NRF2 nuclear translocation and its promoter enrichment on GPX4/xCT, which was reversed by TBHQ. and mutation of the I559 site (I559S) significantly inhibited the DMG-induced ferroptosis of macrophages. In vivo study demonstrated that the administration of DMG via gavage markedly exacerbated atherosclerotic lesion severity, exhibiting elevated the extent of aortic lipid peroxidation, and increased ferroptosis levels in macrophages, which were ameliorated by TBHQ administration.
CONCLUSIONS: DMG inhibits NRF2 nuclear translocation mainly by binding to the I559 site of NRF2 (identified by molecular docking and validated by site-directed mutagenesis), thereby reducing GPX4/xCT expression and promoting macrophage ferroptosis to accelerate AS. Targeting macrophages ferroptosis may serve as a potential intervention strategy for CHD patients with high DMG.