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Shenfu decoction attenuates radiation-induced heart disease by modulating the P53-MDM2 complex and the STAT1-BATF2
Mengyang Wang1, Linxin Zhang1, Wei Liu1
1Department of Pharmacology, College of Pharmacy, Beihua University, Jilin, Jilin 132000, China.
Background:
Radiation-induced heart disease (RIHD) is a common complication of thoracic radiotherapy. Currently, no optimal radioprotective agent is widely available for RIHD treatment. Shenfu Decoction (SFD) has been used as a Traditional Chinese Medicine for thousands of years. Recent studies have shown that SFD can enhance cardiac function. However, the key bioactive compounds in SFD and their underlying mechanisms in RIHD remain unclear.
Objective:
In this study, we investigated the effects of SFD on RIHD.
Methods:
A radiation-induced cardiac injury model was established in C57BL/6 mice using Coγ-rays irradiation. Experimental animals were administered SFD daily for 30 days. RNA sequencing of cardiac tissue was performed to investigate the mechanism of anti-heart injury action of SFD, and potential binding proteins of Kaempferol (KAE), an effective monomer component of SFD, were verified by molecular docking, drug affinity responsive target stability (DARTS), cell thermal shift assay (CETSA) and Surface plasmon resonance assay (SPR).
Results:
SFD significantly improved cardiac function and biochemical parameters in RIHD mice, increasing white blood cell (WBC) and Bone marrow nucleated cell count (BMNC) counts while reducing micronucleus formation and Lactate dehydrogenase (LDH) levels. It also alleviated cardiac hypertrophy and fibrosis. RNA sequencing revealed that this cardioprotective effect was associated with the P53/MDM2-STAT1-BATF2 signaling pathway. Network pharmacology identified KAE as a key active compound, which was confirmed by molecular docking to bind stably with P53. In vitro, KAE inhibited radiation-induced hypertrophy (ANP/BNP), inflammation (IL-6/TNF-α), and apoptosis (TUNEL/Caspase-3) in Neonatal rat ventricular myocytes (NRVMs). Flow cytometry showed KAE induced G2/M arrest in irradiated NRVMs. The data suggest that P53 deficiency in cardiomyocytes abolished the anti-inflammatory effects of KAE. SPR techniques confirmed the binding of KAE and STAT1.
Conclusion:
Our study demonstrates that SFD attenuates radiation-induced cardiac injury, with its protective effects involving the P53/MDM2-STAT1-BATF2 signaling axis. Mechanistically, SFD and its active component kaempferol were found to modulate P53-mediated apoptotic and cell cycle responses, at least in part through interfering with P53-MDM2 interaction and STAT1-driven transcriptional activity. These findings suggest that targeting this signaling axis may represent a promising therapeutic strategy for RIHD.
