Tanshinone IIA attenuates myocardial ischemia by targeting FGFR1 residue Gln284 for allosteric modulation and subsequent autophagy inhibition.

BACKGROUND

Myocardial ischemia (MI) causes diverse pathological injuries, and pharmacological intervention remains a key therapeutic approach. Tanshinone IIA (Tan IIA), a principal active compound derived from the traditional Chinese medicine Danshen, is clinically used in the form of sodium tanshinone IIA sulfonate for the treatment of ischemic heart disease. However, its precise molecular mechanisms and targets are not fully understood.

PURPOSE: This study aimed to explore the targets and mechanisms of Tan IIA against MI in vitro and in vivo.

METHODS

In this study, mouse models of MI induced by left anterior descending artery ligation and isoproterenol were established to validate the therapeutic effects of Tan IIA on MI. We then reanalyzed the GSE1145 dataset of human cardiac tissues and integrated network pharmacology, molecular docking, and phosphoproteomics to screen potential target proteins of Tan IIA. Subsequently, the affinity of Tan IIA for its target was validated using gene knockdown models and multiple techniques, including cellular thermal shift assay, drug affinity responsive target stability assay, biolayer interferometry, and molecular dynamics simulations.

RESULTS

Fibroblast growth factor receptor 1 (FGFR1) was identified as a novel target of Tan IIA, with binding assays showing a specific interaction and a dissociation constant of 13.8 μM. Site-directed mutagenesis further demonstrated that Tan IIA binds directly to the Gln284 residue of FGFR1 and promotes trans-autophosphorylation at Y653/Y654. Mechanistically, Tan IIA activates the downstream FRS2-MAPK pathway to inhibit autophagy, whereas in vitro enzyme assays indicate that it also limits the catalytic turnover of kinase domains. This unique modulatory profile defines Tan IIA as an extracellular domain-directed allosteric modulator that dissociates receptor phosphorylation from steady-state enzymatic flux to effectively provide cardioprotection.

CONCLUSION

This study identifies FGFR1 as a direct molecular target of Tan IIA, establishing a target-specific mechanism underlying its cardioprotective effects and providing a mechanistic basis for the development of precision therapeutic strategies for MI.