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Ruscogenin Alleviates Myocardial Ischemia-Induced Ferroptosis through the Activation of BCAT1/BCAT2
Fei Fu1, Qiong Lai1, Jingui Hu1
1Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
Abstract:
Ruscogenin (RUS), a natural steroidal sapogenin, exerts various biological activities. However, its effectiveness for preventing myocardial ischemia (MI) and its molecular mechanisms need further clarification. The model of MI mice and oxygen-glucose deprivation-induced cardiomyocytes injury was performed. RUS significantly alleviated MI, as evidenced by decreased infarct size, ameliorated biochemical indicators and cardiac pathological features, and markedly inhibited ferroptosis by means of the up-regulation of GPX4 and down-regulation of ACSL4 and FLC. Simultaneously, RUS notably mitigated cell injury and oxidative stress, and ameliorated ferroptosis in vitro. Subsequently, HPLC-Q-TOF/MS-based metabolomics identified BCAT1/BCAT2 as possible regulatory enzymes responsible for the cardioprotection of RUS. Importantly, RUS treatment significantly increased the expression of BCAT1 and BCAT2 in MI. Furthermore, we found that BCAT1 or BCAT2 siRNA significantly decreased cell viability, promoted ferroptosis, and increased Keap1 expression, and induced Nrf2 and HO-1 degradation in cardiomyocytes. Conversely, cardiac overexpression of BCAT1 or BCAT2 in MI mice activated the Keap1/Nrf2/HO-1 pathway. Moreover, RUS significantly activated the Keap1/Nrf2/HO-1 pathway in MI, whereas BCAT1 or BCAT2 siRNA partially weakened the protective effects of RUS, suggesting that RUS might suppress myocardial injury through BCAT1 and BCAT2. Overall, this study demonstrated that BCAT1/BCAT2 could alleviate MI-induced ferroptosis through the activation of the Keap1/Nrf2/HO-1 pathway and RUS exerted cardioprotective effects via BCAT1/BCAT2.
Insights
Ruscogenin (RUS) protects against myocardial ischemia (MI) by inhibiting ferroptosis via BCAT1/BCAT2 and activating the Keap1/Nrf2/HO-1 pathway. This natural sapogenin offers a potential therapeutic strategy for heart injury.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Natural Product Chemistry
Background:
- Myocardial ischemia (MI) remains a leading cause of mortality worldwide.
- Ruscogenin (RUS), a steroidal sapogenin, shows biological activities but its cardioprotective mechanisms are unclear.
- Ferroptosis, an iron-dependent cell death, plays a role in MI pathogenesis.
Purpose of the Study:
- To investigate the efficacy of Ruscogenin (RUS) in preventing myocardial ischemia (MI).
- To elucidate the molecular mechanisms underlying RUS-mediated cardioprotection, focusing on ferroptosis and related pathways.
Main Methods:
- Myocardial ischemia (MI) mouse model and oxygen-glucose deprivation (OGD)-induced cardiomyocyte injury model.
- Assessment of cardiac function, infarct size, and pathological changes.
- HPLC-Q-TOF/MS-based metabolomics to identify key enzymes.
- Gene silencing (siRNA) and overexpression techniques to investigate the role of BCAT1/BCAT2 and the Keap1/Nrf2/HO-1 pathway.
Main Results:
- RUS significantly alleviated MI, reduced infarct size, and improved cardiac function.
- RUS inhibited ferroptosis by up-regulating GPX4 and down-regulating ACSL4 and FLC.
- Metabolomics identified BCAT1/BCAT2 as key enzymes; RUS increased their expression in MI.
- BCAT1/BCAT2 activation by RUS promoted the Keap1/Nrf2/HO-1 pathway, mitigating cardiomyocyte injury and ferroptosis.
Conclusions:
- Ruscogenin (RUS) exerts significant cardioprotective effects against myocardial ischemia (MI).
- RUS alleviates MI by inhibiting ferroptosis through the BCAT1/BCAT2-mediated activation of the Keap1/Nrf2/HO-1 pathway.
- BCAT1 and BCAT2 are crucial mediators of RUS's protective effects in myocardial ischemia.
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