Abstract：
Atherosclerosis is a leading cause of cardiovascular diseases (CVDs), often resulting in major adverse cardiovascular events (MACEs), such as myocardial infarction and stroke due to the rupture or erosion of vulnerable plaques. Ferroptosis, an iron-dependent form of cell death, has been implicated in the development of atherosclerosis. Despite its involvement in CVDs, the specific role of ferroptosis in atherosclerotic plaque stability remains unclear. In this study, we confirmed the presence of ferroptosis in unstable atherosclerotic plaques and demonstrated that the ferroptosis inhibitor ferrostatin-1 (Fer-1) stabilizes atherosclerotic plaques in apolipoprotein E knockout (Apoe-/-) mice. Using bioinformatic analysis combining RNA sequencing (RNA-seq) with single-cell RNA sequencing (scRNA-seq), we identified Yes-associated protein 1 (YAP1) as a potential key regulator of ferroptosis in vascular smooth muscle cells (VSMCs) of unstable plaques. In vitro, we found that YAP1 protects against oxidized low-density lipoprotein (oxLDL)-induced ferroptosis in VSMCs. Mechanistically, YAP1 exerts its anti-ferroptosis effects by regulating the expression of glutaminase 1 (GLS1) to promote the synthesis of glutamate (Glu) and glutathione (GSH). These findings establish a novel mechanism where the inhibition of ferroptosis promotes the stabilization of atherosclerotic plaques through the YAP1/GLS1 axis, attenuating VSMC ferroptosis. Thus, targeting the YAP1/GLS1 axis to suppress VSMC ferroptosis may represent a novel strategy for preventing and treating unstable atherosclerotic plaques.
摘要：
动脉粥样硬化是心血管疾病（CVD）的主要原因，通常导致主要不良心血管事件（MACEs），如由于易损斑块的破裂或侵蚀而导致的心肌梗死和中风。Ferroptosis,一种依赖铁的细胞死亡形式，与动脉粥样硬化的发展有关。尽管它参与了心血管疾病，铁凋亡在动脉粥样硬化斑块稳定性中的具体作用尚不清楚.在这项研究中,我们证实了不稳定动脉粥样硬化斑块中存在铁凋亡,并证明铁凋亡抑制剂铁抑制素-1(Fer-1)可稳定载脂蛋白E基因敲除(Apoe-/-)小鼠的动脉粥样硬化斑块.使用结合RNA测序（RNA-seq）和单细胞RNA测序（scRNA-seq）的生物信息学分析，我们确定Yes相关蛋白1(YAP1)是不稳定斑块的血管平滑肌细胞(VSMC)中铁凋亡的潜在关键调节因子.体外，我们发现YAP1对氧化低密度脂蛋白(oxLDL)诱导的VSMC铁凋亡有保护作用.机械上,YAP1通过调节谷氨酰胺酶1(GLS1)的表达,促进谷氨酸(Glu)和谷胱甘肽(GSH)的合成,发挥其抗铁凋亡作用。这些发现建立了一种新的机制，其中铁凋亡的抑制通过YAP1/GLS1轴促进动脉粥样硬化斑块的稳定，衰减VSMC铁中毒。因此，靶向YAP1/GLS1轴以抑制VSMC铁蛋白凋亡可能是预防和治疗不稳定动脉粥样硬化斑块的新策略.
