Yang Yunfan, Chen Zhenzhen, Song Dandan, Wu Junduo, Wang Junnan
Department of Cardiology, Second Hospital of Jilin University, Changchun, Jilin 130041, China.
Department of Clinical Laboratory, Second Hospital of Jilin University, No. 218 Ziqiang Street, Changchun 130041, China.
Int Immunopharmacol. 2025 Apr 24;153:114553. doi: 10.1016/j.intimp.2025.114553. Epub 2025 Mar 26.
Atherosclerosis (AS) is a lipid disorder characterised by lipid accumulation in the aortic wall and foam cell formation. Recent studies have shown that excess iron accelerates AS progression and foam cell formation by inducing ferroptosis. GPx4, an anti-erroptotic protein, promotes SCARB1 expression, which inhibits macrophage foam cell formation by interacting with HDL. Thus, a complex association exists between ferroptosis and lipid metabolism. However, the underlying mechanisms remain unclear. AMPK signalling is a key regulator of metabolism and is involved in the regulation of ferroptosis. In this study, we used the ferroptosis inhibitor ferrostatin-1 (Fer-1) to assay the effect of ferroptosis inhibition on AS and foam cell formation and to investigate the underlying mechanism. Our results showed that Fer-1 alleviated AS lesions and foam cell formation both in vivo and in vitro. Additionally, Fer-1 reduced iron content and lipid accumulation in oxidized low-density lipoprotein (ox-LDL)-treated macrophages by upregulating the levels of FTH, GPx4, and SCARB1 via AMPK activation. The inhibition of AMPK reduces the effect of Fer-1 on iron and lipid accumulation in macrophages, which may contribute to a deeper understanding of the pathological process of AS and provide a therapeutic target for AS.
动脉粥样硬化（AS）是一种脂质紊乱疾病，其特征是脂质在主动脉壁中积累并形成泡沫细胞。最近的研究表明，过量的铁通过诱导铁死亡加速AS进展和泡沫细胞形成。GPx4是一种抗铁死亡蛋白，可促进SCARB1表达，SCARB1通过与高密度脂蛋白（HDL）相互作用抑制巨噬细胞泡沫细胞形成。因此，铁死亡与脂质代谢之间存在复杂的关联。然而，其潜在机制仍不清楚。AMPK信号通路是代谢的关键调节因子，参与铁死亡的调节。在本研究中，我们使用铁死亡抑制剂铁抑素-1（Fer-1）来检测铁死亡抑制对AS和泡沫细胞形成的影响，并研究其潜在机制。我们的结果表明，Fer-1在体内和体外均减轻了AS病变和泡沫细胞形成。此外，Fer-1通过激活AMPK上调FTH、GPx4和SCARB1的水平，降低了氧化型低密度脂蛋白（ox-LDL）处理的巨噬细胞中的铁含量和脂质积累。抑制AMPK会降低Fer-1对巨噬细胞中铁和脂质积累的影响，这可能有助于更深入地了解AS的病理过程，并为AS提供治疗靶点。
