RESUMEN

BACKGROUND: Doxorubicin (DOX) is a potent anticancer medication, but its significant cardiotoxicity poses a challenge in clinical practice. Galangin (Gal), a flavonoid compound with diverse pharmacological activities, has shown potential in exerting cardioprotective effects. However, the related molecular mechanism has not been fully elucidated. PURPOSE: Combined with bioinformatics and experimental verification methods to investigate Gal's potential role and underlying mechanisms in mitigating DOX-induced cardiotoxicity (DIC). METHODS: C57BL/6 mice received a single dose of DOX via intraperitoneal injection 4 days before the end of the gavage period with Gal. Myocardial injury was evaluated using echocardiography, myocardial injury biomarkers, Sirius Red and H&E staining. H9c2 cells were stimulated with DOX to mimic DIC in vitro. The potential therapeutic target of Gal was identified through network pharmacology, molecular docking and cellular thermal shift assay (CETSA), complemented by an in-depth exploration of the GSTP1/JNK signaling pathway using immunofluorescence. Subsequently, the GSTP1 inhibitor Ezatiostat (Eza) substantiated the signaling pathway. RESULTS: Gal administration considerably raised DOX-inhibited the left ventricular ejection fractions (LVEF), reduced levels of myocardial injury markers (c-TnI, c-TnT, CKMB, LDH, and AST), and alleviated DOX-induced myocardial histopathological injury and fibrosis in mice, thereby improving cardiac dysfunction. The ferroptosis induced by DOX was inhibited by Gal treatment. Gal remarkably ameliorated the DOX-induced lipid peroxidation, accumulation of iron and Ptgs2 expression both in H9c2 cells and cardiac tissue. Furthermore, Gal effectively rescued the DOX-inhibited crucial regulators of ferroptosis such as Gpx4, Nrf2, Fpn, and Slc7a11. The mechanistic investigations revealed that Glutathione S-transferase P1 (GSTP1) may be a potential target for Gal in attenuating DIC. Gal act on GSTP1 by stimulating its expression, thereby enhancing the interaction between GSTP1 and c-Jun N-terminal kinase (JNK), leading to the deactivation of JNK/c-Jun pathway. Furthermore, interference of GSTP1 with inhibitor Eza abrogated the cardioprotective and anti-ferroptotic effects of Gal, as evidenced by decreased cell viability, reduced expression of GSTP1 and Gpx4, elevated MDA levels, and promoted phosphorylation of JNK and c-Jun compared with Gal treatment. CONCLUSION: Gal could inhibit ferroptosis and protect against DIC through regulating the GSTP1/JNK pathway. Our research has identified a novel pathway through which Gal regulates DIC, providing valuable insights into the potential therapeutic efficacy of Gal in mitigating cardiotoxic effects.