Targeting LTBP2 Reveals a Novel Anti-Cardiac Remodeling Mechanism of Finerenone Against Doxorubicin-Induced Cardiotoxicity.

Despite the clinical efficacy of doxorubicin (DOX), effective strategies to prevent its cardiotoxicity are still lacking. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist (MRA), has demonstrated cardioprotective properties; however, its role and mechanism in DOX-induced cardiotoxicity (DIC) remain unclear. In this study, Finerenone treatment was found to significantly alleviate DOX-induced cardiac dysfunction and pathological remodeling in both mouse models and cultured cells. Mechanistically, molecular docking suggests that Finerenone may directly bind to Latent Transforming Growth Factor Beta Binding Protein 2 (LTBP2), a key regulator of TGF-β bioavailability. This potential binding could inhibit the LTBP2-TGF-β axis, thereby suppressing DOX-induced activation and subsequent Smad3 phosphorylation. The importance of this pathway was supported by the similar anti-fibrotic effects observed with the TGF-β inhibitor LY2109761. However, our findings on the direct binding of Finerenone to LTBP2 are preliminary and require further validation through additional experimental approaches. These results identify LTBP2 as a novel direct target of Finerenone and reveal an additional mechanism underlying its cardioprotective action, suggesting its potential repurposing for the prevention of DIC.