Abstract Body (Do not enter title and authors here): Introduction: Sunitinib, a multi-targeted tyrosine kinase inhibitor, is approved for the treating several advanced solid tumors. However, its clinical application is severely limited by cardiotoxicity, particularly myocardial fibrosis. Oridonin, a natural diterpenoid compound, has emerged as a promising candidate due to its potential antifibrotic properties.
Objectives: This study aimed to investigate the protective effects of oridonin against sunitinib-induced cardiotoxicity and elucidate its potential mechanism for inhibiting myocardial fibrosis.
Methods: A mouse model of sunitinib-induced cardiotoxicity was established by oral gavage administration of sunitinib (40 mg/kg/day) for 8 weeks. Concurrently, oridonin (2.5, 5, or 10 mg/kg/day) was administered via intraperitoneal injection. Cardiac function was assessed using echocardiography. Untargeted metabolomic profiling was performed using liquid chromatography-mass spectrometry . Heart tissues underwent single-nucleus RNA sequencing (snRNA-seq) for transcriptomic analysis. Protein expression was analyzed using Western blotting.
Results: Sunitinib administration significantly decreased left ventricular ejection fraction (LVEF), an effect rescued by oridonin treatment. Untargeted metabolomics revealed increased levels of lipid-related metabolites in the sunitinib group, which were reduced by oridonin. snRNA-seq analysis demonstrated a significant increase in fibroblasts within the SUNI group, correlating with alterations in lipid metabolism regulation. Gene Ontology (GO) analysis of fibroblasts identified elevated expression of fatty acid binding protein 4 (FABP4) in the SUNI group, which was attenuated by oridonin. Molecular docking indicated that oridonin binds to fibroblast growth factor receptor 1 (FGFR1), potentially activating extracellular signal-regulated kinases 1/2 (ERK1/2) and subsequently suppressing the proliferator-activated receptor-gamma (PPARγ)/FABP4/transforming growth factor-β1 (TGF-β1) signaling pathway. Crucially, FGFR1 knockdown using siRNA abolished oridonin's suppressive effect on FABP4 expression.
Conclusion: This study demonstrates that oridonin mitigates sunitinib-induced myocardial fibrosis by selectively inhibiting the PPARγ/FABP4/TGF-β1 axis. These findings provide a novel strategy for managing cardiotoxicity during cancer therapy and suggest that natural compound-based combination therapies represent a viable approach to balancing antitumor efficacy and cardiovascular safety.