Salidroside can protect against ferroptosis in cardiomyocytes and may be related to the regulation of GGT1

Tianhang Feng¹Qin Zhao²Jing Shi²Jinghua Zhao²Tao Wang³Sha Wan²Chen Fan²Sijia Wang¹Chunyou Lai¹Yutong Yao^1*

• ¹Sichuan Provincial Hospital, Chengdu, China
• ²Hospital of Chengdu Office of People’s Government of Tibetan Autonomous Region (Hospital.C.T.), Chengdu, China
• ³University of Electronic Science and Technology of China, Chengdu, Sichuan Province, China

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 in vitro (RSL3-induced H9C2 cardiomyocytes) and in vivo (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.