Characterized by the death of cardiomyocytes, myocardial infarction (MI) represents an acute and critical clinical situation commonly encountered. This leads to the permanent loss of cardiac functional units (Del et al., 2019), resulting in several cardiac structural and functional alterations. Such transformations inevitably instigate the initiation and progression of cardiovascular diseases (CVDs), encompassing ventricular remodeling as well as heart failure (Dorn, 2009; Marunouchi and Tanonaka, 2015; Moe and Marín-García, 2016). Therefore, effectively inhibiting cardiomyocyte death after MI remains a major challenge that needs to be addressed.

Ferroptosis, one of the programmed cell death forms, shows the features of abnormal lipid metabolism and intracellular iron overload (Li et al., 2020). The recent revelation that ferroptosis contributes to the progression of CVDs, such as ischemic cardiovascular disease, represents a significant advancement in this field (Li et al., 2021). In the case of ischemia, the myocardium can accumulate excess iron and reactive oxygen species (ROS), and pathological changes in membrane lipids, constituting a vital factor of ferroptosis (Han et al., 2023; Zhao et al., 2021). The myocardium also manifests the relevant ferroptosis characteristics, some examples including oxidative stress, endoplasmic reticulum stress, iron overload, and mitochondrial dysfunction (Han et al., 2023; Zhao et al., 2021). Consistent with our preceding research (Wu et al., 2023), inhibitors of ferroptosis or agents that chelate iron have the potential to elevate cardiac functionality and are effective in the prevention and treatment of myocardial damage and heart failure induced by ferroptosis (Li et al., 2021; Wang and Kang, 2021). Hence, ferroptosis accounts for a critical cardiomyocyte death pattern and is vital for mediating myocardial damage after ischemic cardiovascular disease.

NF-E2 p45-related factor 2 (Nrf2), a pivotal transcriptional factor, is implicated in the progression of unfavorable ventricular remodeling and potentially heart failure following MI. This is evidenced by significantly enlarged infarct areas in mice with Nrf2 expression knockout or inhibition (Strom and Chen, 2017; Vashi and Patel, 2021). Nrf2 is also a critical factor in the inhibition of lipid peroxidation and ferroptosis (Dodson et al., 2019) and is an essential cardiomyocyte ferroptosis regulator (Wang et al., 2022). The two primary targets for ferroptosis inhibition are glutathione peroxidase 4 (GPX4) and the cystine-glutamate transport receptor (xCT), both of which are regulated by Nrf2 (Tonelli et al., 2018). GPX4, as an indispensable antioxidase, uses glutathione (GSH) as a substrate to reduce and obstruct the accumulation of lipid ROS, thereby impeding ferroptosis triggered by lipid peroxidation (Rochette et al., 2022). This aligns with earlier research indicating that GPX4 downregulation during MI leads to the ferroptosis of cardiomyocytes (Park et al., 2019). Furthermore, xCT, the transporter of amino acids existing onto cell membrane, can import cystine while exporting glutamate, promoting GSH production (Tu et al., 2021). Thus, erastin, the typical inhibitor of xCT, can eliminate intracellular GSH, reduce GPX4 activity, and iron-dependently enhance lipid peroxide contents on the membrane, causing ferroptosis occurrence. In our previous research, we discovered that erastin induces ferroptosis in cardiomyocytes. Meanwhile, ferroptosis inhibitors have been shown to suppress MI. Importantly, erastin mediates the ferroptosis of cardiomyocytes by inhibiting the expression of xCT and GPX4 (Wu et al., 2023). Moreover, prior research has demonstrated that the Nrf2/xCT/GPX4 axis exhibits an inhibitory effect on cardiomyocytes ferroptosis and provides protection against myocardial damage following MI (Shen et al., 2022). Thus, it is clear that xCT and GPX4, as Nrf2 target genes, may play an essential part in post-MI cardiomyocyte ferroptosis. Implementing the Nrf2 signaling pathway to reduce ferroptosis in cardiomyocytes and alleviate myocardial damage after MI could potentially serve as an effective treatment approach for CVDs.

Salvia miltiorrhiza Bunge (DS) is considered as a typical medicine that helps enhance blood circulation while alleviating blood stasis during CVDs management (Li et al., 2018). Pharmacological studies found that DS exerts antioxidant effects, inhibits lipid peroxide and left ventricular remodeling, improves cardiac ischemic injury, and protects heart function (Li et al., 2018; MEIm et al., 2019). Given that ferroptosis exhibits characteristic features, such as the production of ROS and iron-dependent lipid peroxidation, we are inclined to investigate whether DS could leverage its cardioprotective effects against MI through inhibiting ferroptosis. Recent studies have indeed begun to establish a connection between DS and ferroptosis. It has been discovered that DS mitigates oxidative stress-induced ferroptosis of photoreceptors in retinitis pigmentosa (Yang et al., 2023). Moreover, 15,16-Dihydrotanshinone I, a bioactive component extracted from DS, has been identified to confer protection against ischemic stroke by suppressing ferroptosis (Wu et al., 2023). However, the potential of DS in inhibiting post-MI cardiomyocyte ferroptosis and mitigating myocardial damage requires further investigation. Thus, to examine the impact of DS on combating cardiomyocyte ferroptosis and ameliorating post-MI myocardial damage, we employed an in vivo MI animal model constructed through ligation of the left anterior descending coronary artery, alongside an in vitro model of H9C2 cell ferroptosis induced by erastin. Additionally, the possible Nrf2 signaling-induced protection was also analyzed.