Myocardial ischemia-reperfusion injury (MIRI) is a complex physiological and pathological process that may occur after the recovery of cardiac blood supply. This is due to the injury that occurs when blocked coronary vessels are reopened by thrombolysis, interventional therapy, or bypass surgery to restore blood flow to the heart [1,2]. Currently, treatments for this injury include pharmacological treatments, mechanical treatments, and novel nanocarrier drug delivery systems [[3], [4], [5], [6]]. However, the trigger mechanism of MIRI is very complex, covering many aspects, such as the increase of the level of oxygen free radicals, inflammation, disturbance of energy metabolism, and excessive intracellular calcium accumulation. It is worth noting that cardiomyocyte ferroptosis, as a newly discovered form of regulating cell death dependent on iron and reactive oxygen species, is closely related to the occurrence of MIRI [7]. In the process of MIRI, cardiomyocytes may experience ferroptosis, resulting in serious damage to cell structure and function [8,9]. The regulation of ferroptosis can be used as a promising treatment to alleviate MIRI.

Ferroptosis is an iron-dependent mode of cell death, which directly or indirectly affects the activity of glutathione peroxidase (GPXs) under the induction of small molecules, leading to membrane lipid peroxidation, redox imbalance, excessive accumulation of ROS, and ultimately cell death. Generally speaking, the triggering of ferroptosis during ischemia and reperfusion phases has the potential to intensify MIRI [10,11]. Studies have shown that in the myocardial ischemia/reperfusion (I/R) model, lipid peroxidation occurs, leading to an increase in ROS levels, abnormal intracellular iron levels, and decreased levels of anti-lipid peroxidation-related enzymes such as GPX4 [12,13]. Furthermore, the application of ferroptosis inhibitors can significantly improve cardiac dysfunction caused by I/R injury [14]. Ferroptosis, which has been established as a novel mode of non-apoptotic cell death, is closely related to MIRI.

E26 transcription factor (E26 transformation specific-1, ETS-1) plays a regulatory role of key genes in many physiology and pathology [15]. Studies have discovered that ETS1 is capable of upregulating the expression of the Xc-cystine glutamate transporter (SLC7A11, xCT), which is a crucial upstream regulator of ferroptosis. It is responsible for the transport of cystine into cells and then reduced to cysteine, which is an important raw material for the synthesis of glutathione (GSH) [16,17]. GSH is the main antioxidant in cells, which can protect cells from oxidative stress and ferroptosis [18]. PIM3 is a kinase belonging to the PIM family. It has serine/threonine kinase activity and plays a critical role in cell growth and survival [19]. In addition, it has been reported that ETS1 can significantly regulate the expression of downstream molecules PIM3 [20,21]. However, whether ETS1 mediates the regulation of ferroptosis in MIRI through PIM3 remains unexplored.

Therefore, in this study, we aimed to explore the molecular mechanism of ETS1 regulation of PIM3 mediated ferroptosis, clarify the influence of ETS1 on MIRI process, and provide theoretical basis and scientific basis for subsequent MIRI treatment.