Forsythiaside B alleviates DOX-induced myocardial injury by enhancing the interaction between HSP90AA1 and CYP1A1 to inhibit ferroptosis.
Abstract
Background
Doxorubicin (DOX) is a potent anti-tumor drug that is commonly associated with cardiotoxic reactions (DIC) during its use. Ferroptosis in cardiomyocytes is one of the key pathogenic mechanisms of this toxic reaction. Forsythiaside B (FTB) has been proven to have cardioprotective effects, but its role and potential mechanism in DIC remain unknown.
Methods
The DOX treatment was applied to mouse and neonatal rat cardiomyocytes (NRCMs) to establish in vivo and in vitro models of DIC, in order to verify the cardioprotective effect of FTB. Meanwhile, the molecular targets of FTB were determined through proteomics, molecular docking, and molecular dynamics simulations to explore the mechanism of FTB's action. Additionally, a breast cancer xenograft model was constructed by subcutaneous injection of 4T1 cells to evaluate the impact of FTB on the anti-tumor efficacy of DOX.
Results
Our study reveals that FTB inhibits DOX-induced ferroptosis and myocardial cell damage. Moreover, when DOX-induced ferroptosis was inhibited by ferroptosis inhibitor Fer-1, FTB was unable to further inhibit DOX-induced cardiomyocyte ferroptosis and injury, indicating that FTB alleviates DOX-induced myocardial cell damage by inhibiting ferroptosis. Mechanistically, FTB directly targets heat shock protein 90 alpha family class A member 1 (HSP90AA1) and cytochrome P450 1A1 (CYP1A1), enhances the interaction between HSP90AA1 and CYP1A1, and promotes the ubiquitination and degradation of CYP1A1 mediated by HSP90AA1-STUB1 complex. Overexpression of CYP1A1 and selective inhibition of HSP90AA1 weaken the inhibitory effect of FTB on ferroptosis and its cardioprotective effect against DIC. More importantly, the application of FTB does not affect the antitumor efficacy of DOX.
Conclusion
In summary, FTB enhances the interaction between HSP90AA1 and CYP1A1 to inhibit ferroptosis, thereby alleviating DOX-induced myocardial damage. This discovery presents a highly promising therapeutic strategy for the treatment of DIC.