Atherosclerosis is a chronic vascular disease closely associated with endothelial dysfunction.Ferroptosis,a major factor in endothelial dysfunction,plays a pivotal role in the progression of atherosclerosis.The develo...Atherosclerosis is a chronic vascular disease closely associated with endothelial dysfunction.Ferroptosis,a major factor in endothelial dysfunction,plays a pivotal role in the progression of atherosclerosis.The development of drugs targeting endothelial ferroptosis offers a potential therapeutic approach for atherosclerosis.This study aimed to assess the potential impact of tetrahydroberberrubine(THBru)on atherosclerosis and unravel its molecular mechanism underlying endothelial protection.Our results demonstrated that THBru significantly reduced plaque formation in the aortas of atherosclerotic mice.Through transcriptome sequencing and further verification,we observed that THBru mitigated endothelial ferroptosis in atherosclerosis by enhancing glutathione homeostasis and decreasing reactive oxygen species(ROS)accumulation.Mechanistically,bioinformatic analysis demonstrated that THBru reduced the expression of the super-enhancer(SE)regulatory gene ATP-binding cassette subfamily C member 1(ABCC1).The transcription factor BTB and CNC homology 1(BACH1)was responsible for ABCC1 transcription by binding to its SE(ABCC1-SE),whereas THBru effectively inhibited the activity of ABCC1-SE.Furthermore,THBru promoted adenosine monophosphate-activated protein kinase(AMPK)activation,thereby negatively regulating BACH1 and the downstream ABCC1/ferroptosis signaling pathway.Collectively,these findings highlight THBru as a promising candidate for treating atherosclerosis,featuring a novel mechanism that inhibits endothelial ferroptosis through the AMPK/BACH1 axis to regulate ABCC1-SE.展开更多
基金supported by the Noncommunicable Chronic Diseases National Science and Technology Major Project(2024ZD0537908,China)the National Natural Science Foundation of China(82273919,82270396,82570453,82500553,U24A20813 and U21A20339)the Science Foundation for the Excellent Youth Scholars of Heilongjiang Province(JJ2023YX0509,China).
文摘Atherosclerosis is a chronic vascular disease closely associated with endothelial dysfunction.Ferroptosis,a major factor in endothelial dysfunction,plays a pivotal role in the progression of atherosclerosis.The development of drugs targeting endothelial ferroptosis offers a potential therapeutic approach for atherosclerosis.This study aimed to assess the potential impact of tetrahydroberberrubine(THBru)on atherosclerosis and unravel its molecular mechanism underlying endothelial protection.Our results demonstrated that THBru significantly reduced plaque formation in the aortas of atherosclerotic mice.Through transcriptome sequencing and further verification,we observed that THBru mitigated endothelial ferroptosis in atherosclerosis by enhancing glutathione homeostasis and decreasing reactive oxygen species(ROS)accumulation.Mechanistically,bioinformatic analysis demonstrated that THBru reduced the expression of the super-enhancer(SE)regulatory gene ATP-binding cassette subfamily C member 1(ABCC1).The transcription factor BTB and CNC homology 1(BACH1)was responsible for ABCC1 transcription by binding to its SE(ABCC1-SE),whereas THBru effectively inhibited the activity of ABCC1-SE.Furthermore,THBru promoted adenosine monophosphate-activated protein kinase(AMPK)activation,thereby negatively regulating BACH1 and the downstream ABCC1/ferroptosis signaling pathway.Collectively,these findings highlight THBru as a promising candidate for treating atherosclerosis,featuring a novel mechanism that inhibits endothelial ferroptosis through the AMPK/BACH1 axis to regulate ABCC1-SE.
