铁稳态失衡所导致的铁死亡是心肌缺血再灌注损伤(IRI)早期主要的驱动因素，并与糖尿病的发生发展密切相关。我们预实验发现糖尿病早期心肌铁稳态相关因子TfR1表达增加且节律紊乱，铁死亡关键蛋白ACSL4表达增加，而铁死亡抑制剂显著抑制上述变化，并减轻心肌IRI，但其机制未明。研究表明铁稳态具有节律性且与核心时钟基因密切相关，REV-ERBα负性调控BMAL1/CLOCK是维持生物钟节律准确性的关键枢纽。我们前期研究显示糖尿病心肌BMAL1表达降低且更不易耐受IRI；进一步预实验发现糖尿病心肌IRI期间REV-ERBα振荡失调而BMAL1表达下降。据此，我们推测REV-ERBα振荡调控的铁死亡是糖尿病心肌IRI加重的关键机制之一。本项目拟在敲除小鼠在体及原代心肌细胞上，探讨REV-ERBα振荡调控的铁死亡在糖尿病心肌再灌注易损性增加中的机制，为糖尿病心肌IRI的药物防治和早期干预策略提供新靶点。

Ferroptosis, caused by imbalance of iron homeostasis, is a primary driver of myocardial ischemia reperfusion injury (IRI) and is closely related to the occurrence and development of diabetes. Our preliminary study found that the expression of iron homeostasis related factor TfR1 was increased, which was accompanied with TfR1 rhythm disorder in diabetic myocardium; the level of ferroptosis key protein ACSL4 was increased. While ferroptosis inhibitor could significantly inhibit these changes and significantly reduce myocardial IRI. However, the specific underlying mechanisms are still unclear. Studies have shown that iron homeostasis is rhythmic and closely related to the core clock gene. REV-ERBα mediated negative regulation of BMAL1/CLOCK is pivotal for the maintenance of the accuracy of circadian clock rhythm. Our recent study indicated that the expression of BMAL1 in diabetic myocardium was decreased with increased vulnerability to IRI. Our further preliminary study showed that the oscillation of REV-ERBα was disordered with decreased expression of BMAL1 protein during diabetic myocardial IRI. Accordingly, we speculate that ferroptosis regulated by REV-ERBα oscillation plays a key role in increased vulnerability to myocardial IRI in diabetes. In this proposal, we will use gene knockout mice and primarily cultured cardiomyocytes to investigate the mechanism of REV-ERBα oscillation modulated ferroptosis in increased vulnerability to IRI in diabetic hearts in vitro and in vivo study. This proposed studies may help facilitate the development of potential and novel therapies or primary intervention in combating ischemic heart disease in diabetes.