Fu Jiaqi, Liu Hongyu, Liang Yuqin, Shi Yunhe, Gao Xin, Chen Pingping, Yu Donghua, Wang Yu, Lu Fang, Liu Shumin
Institute of Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China; Wenzhou Medical University, Wenzhou, Zhejiang, China.
Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
J Ethnopharmacol. 2025 Mar 26;344:119507. doi: 10.1016/j.jep.2025.119507. Epub 2025 Feb 18.
Chinese medicine, specifically Huangqi Chifeng Decoction (HQCF), is recognized for its efficacy in treating atherosclerosis (AS), a common cardiovascular disease. Despite its established benefits in addressing Qi deficiency, blood stasis, and collateral obstruction, the precise mechanism through which HQCF affects AS remains unclear.
This study investigated the potential of HQCF to mitigate AS by suppressing smooth muscle cell (SMC) foam formation through the ferroptosis pathway.
An AS model was established using ApoE mice fed a high-fat diet (HFD), and the role of HQCF in regulating ferroptosis in AS was examined. Using a single-cell proteomics analysis strategy, we identified the primary targets of HQCF in SMCs. Additionally, an oxidized low-density lipoprotein (ox-LDL)-treated SMC-derived foam cell model was established. The effects HQCF on SMC ferroptosis were analyzed, and ox-LDL-induced SMCs were pretreated with small interfering RNA (siRNA) and overexpressing carrier plasmids (pcDNA) to identify potential therapeutic targets, for specifically thioredoxin (TXN).
HQCF the pathological state of the aorta in ApoE mice, regulated lipid levels, improved antioxidant capacity, modulated the phenotypic transformation of SMCs, and maintained the dynamic balance of extracellular matrix degradation and remodeling. Additionally, HQCF may inhibit ferroptosis via positive regulation of the GPX4/xCT signaling pathway. Single-cell proteomics revealed 36 common differentially expressed proteins (DEPs), suggesting that HQCF's treatment of AS may be associated with the regulation of cellular function and redox homeostasis. The abnormal expression of TXN in SMCs may be related to the phenotypic transition induced by AS. HQCF was also found to ameliorate oxidative stress and mitochondrial dysfunction during SMC foaming. Moreover, ferroptosis was involved in ox-LDL-induced foam cell formation, and HQCF alleviated these pathologies by inhibiting ferroptosis. The protective effect of HQCF on SMCs was enhanced by TXN overexpression but partially reversed by TXN knockdown, further indicating that HQCF's regulation of SMC function and inhibition of ferroptosis is, at least in part, mediated by TXN.
These findings suggest that HQCF protects SMCs from ferroptosis by regulating the TXN/xCT/GPX4 pathway, ameliorating the aortic pathological state, alleviating oxidative stress, and maintaining mitochondrial homeostasis in mice.
中药，特别是黄芪赤风汤（HQCF），因其在治疗动脉粥样硬化（AS）这一常见心血管疾病方面的功效而受到认可。尽管其在解决气虚、血瘀和络阻方面已证实具有益处，但HQCF影响AS的确切机制仍不清楚。
本研究通过铁死亡途径抑制平滑肌细胞（SMC）泡沫形成，探讨HQCF减轻AS的潜力。
使用喂食高脂饮食（HFD）的ApoE小鼠建立AS模型，并研究HQCF在调节AS中铁死亡中的作用。采用单细胞蛋白质组学分析策略，我们确定了HQCF在SMC中的主要靶点。此外，建立了氧化低密度脂蛋白（ox-LDL）处理的SMC来源的泡沫细胞模型。分析了HQCF对SMC铁死亡的影响，并用小干扰RNA（siRNA）和过表达载体质粒（pcDNA）预处理ox-LDL诱导的SMC，以确定潜在的治疗靶点，特别是硫氧还蛋白（TXN）。
HQCF改善了ApoE小鼠主动脉的病理状态，调节了血脂水平，提高了抗氧化能力，调节了SMC的表型转化，并维持了细胞外基质降解和重塑的动态平衡。此外，HQCF可能通过正向调节GPX4/xCT信号通路抑制铁死亡。单细胞蛋白质组学揭示了36种常见的差异表达蛋白（DEP），表明HQCF对AS的治疗可能与细胞功能和氧化还原稳态的调节有关。SMC中TXN的异常表达可能与AS诱导的表型转变有关。还发现HQCF可改善SMC泡沫化过程中的氧化应激和线粒体功能障碍。此外，铁死亡参与了ox-LDL诱导的泡沫细胞形成，HQCF通过抑制铁死亡减轻了这些病理变化。TXN过表达增强了HQCF对SMC的保护作用，但TXN敲低部分逆转了这种作用，进一步表明HQCF对SMC功能的调节和对铁死亡的抑制至少部分是由TXN介导的。
这些发现表明，HQCF通过调节TXN/xCT/GPX4途径保护SMC免受铁死亡，改善主动脉病理状态，减轻氧化应激，并维持小鼠线粒体稳态。
