Feng Tianhang, Shi Jing, Zhao Jinghua, Zhao Qin, Wang Tao, Wan Sha, Fan Chen, Wang Sijia, Lai Chunyou, Yao Yutong
Department of International Medical, Sichuan Provincial Hospital, University of Electronic Science and Technology of China, Chengdu, China.
Science and Education Section, Hospital of Chengdu Office of People's Government of Xizang Autonomous Region (Hospital.C.X.), Chengdu, China.
Front Pharmacol. 2025 May 14;16:1580506. doi: 10.3389/fphar.2025.1580506. eCollection 2025.
Ferroptosis, an iron-dependent cell death mechanism driven by lipid peroxidation, represents a novel therapeutic target for myocardial injury. Salidroside (SAL), a natural bioactive compound derived from Rhodiola rosea, exhibits cardioprotective effects through multi-target mechanisms with minimal adverse effects, yet its precise role in ferroptosis regulation remains unclear.
This study systematically investigated SAL's anti-ferroptotic effects using (RSL3-induced H9C2 cardiomyocytes) and (DOX-induced myocardial injury mouse model) approaches.
SAL treatment significantly enhanced cardiomyocyte viability by attenuating ferroptotic hallmarks, including lipid ROS accumulation, iron overload, lipid peroxidation, and mitochondrial dysfunction. Transcriptomic analysis revealed SAL-mediated modulation of DNA replication/repair, cell cycle regulation, protein autophosphorylation, drug ADME processes, and glutathione metabolism-a critical pathway in ferroptosis. Molecular docking identified γ-glutamyltransferase 1 (GGT1) as a high-affinity SAL target, linking drug metabolism and glutathione homeostasis. In MI mice, SAL downregulated GGT1 expression while restoring ferroptosis-related biomarkers: upregulating GPX4 and reducing SLC7A11/LC3II levels. Mechanistically, SAL suppresses ferroptosis through dual regulation of GGT1: (1) enhancing glutathione synthesis via GGT1 inhibition and (2) potentiating GPX4-mediated antioxidant defense.
These findings establish GGT1 as a pivotal therapeutic target for SAL's cardioprotection, providing a mechanistic basis for its clinical application in ferroptosis-associated cardiovascular diseases.
铁死亡是一种由脂质过氧化驱动的铁依赖性细胞死亡机制，是心肌损伤的一个新的治疗靶点。红景天苷（SAL）是一种从红景天中提取的天然生物活性化合物，通过多靶点机制发挥心脏保护作用，副作用极小，但其在铁死亡调节中的具体作用尚不清楚。
本研究使用（RSL3诱导的H9C2心肌细胞）和（阿霉素诱导的心肌损伤小鼠模型）方法系统地研究了SAL的抗铁死亡作用。
SAL治疗通过减轻铁死亡特征，包括脂质活性氧积累、铁过载、脂质过氧化和线粒体功能障碍，显著提高心肌细胞活力。转录组分析显示SAL介导了对DNA复制/修复、细胞周期调节、蛋白质自磷酸化、药物ADME过程和谷胱甘肽代谢（铁死亡中的关键途径）的调节。分子对接确定γ-谷氨酰转移酶1（GGT1）是SAL的高亲和力靶点，将药物代谢与谷胱甘肽稳态联系起来。在心肌梗死小鼠中，SAL下调GGT1表达，同时恢复铁死亡相关生物标志物：上调GPX4并降低SLC7A11/LC3II水平。机制上，SAL通过对GGT1的双重调节抑制铁死亡：（1）通过抑制GGT1增强谷胱甘肽合成；（2）增强GPX4介导的抗氧化防御。
这些发现确立了GGT1是SAL心脏保护作用的关键治疗靶点，为其在铁死亡相关心血管疾病中的临床应用提供了机制基础。
