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

INDRODUCTION

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.

METHODS

This study systematically investigated SAL's anti-ferroptotic effects using (RSL3-induced H9C2 cardiomyocytes) and (DOX-induced myocardial injury mouse model) approaches.

RESULTS

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.

DISCUSSION

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.