Diabetes mellitus (DM) is on the verge of becoming a global epidemic. According to a report by the International Diabetes Federation, DM currently affects nearly 4250 million people [
1]. In China, DM affects 10.9% of the population, which accounts for about a third of the diabetic patients worldwide [
2]. Cardiovascular complications are the primary cause of disability and death due to DM. The medical expenses associated with diabetic macrovascular complications accounts for 80% of the total amount, making DM a huge economic burden on the society [
3]. Therefore, it is imperative to prevent or delay the onset and development of diabetic cardiovascular complications. Diabetic cardiomyopathy (DCM), a major complication associated with DM, is defined as the dysfunction of the left ventricle in diabetic patients, in the absence of coronary artery disease or hypertension [
4,
5]. It is initially characterized by left ventricular diastolic dysfunction and interstitial fibrosis, followed by systolic dysfunction and ejection fraction, and eventually resulting in heart failure [
5‐
7]. Notably, cardiomyocyte apoptosis plays an important role in the pathophysiological mechanisms associated with DCM. There are two major mechanisms regulating this apoptosis. The first mechanism involves an intrinsic pathway, also called ‘the mitochondrion pathway’, such as the one regulating the B cell lymphoma/leukemia-2 (Bcl-2) protein family. The other apoptosis mechanism occurs via signaling by death receptor members, such as factor associated suicide (Fas)/factor associated suicide ligand (Fas-L) [
8]. Hyperglyceamia activates the protein 53 (p53), and the renin-angiotensin system (RAS), resulting in the production of angiotensin II (Ang II), which leads to a decrease in Bcl-2 expression and an increase in Bcl-2 associated X protein (Bax) expression and, thus, plays an important role in promoting apoptosis [
9,
10]. Bcl-2 and Bax are key proteins that regulate apoptosis [
11]. P53 is a tumour suppressor gene that induces apoptosis by blocking cellular DNA damage repair [
12]. Fas/FasL signaling is also crucial for cardiomyocyte apoptosis as it mainly regulates caspase-3 [
13]. Currently, Western medicine is mainly focused on glycaemic control and treatment or prevention of risk factors associated with cardiovascular disease; however, these approaches do not fundamentally solve the problem of cardiac dysfunction [
4,
14,
15].
Sheng Mai San (SMS) is a classical traditional Chinese formula containing the root of
Radix Ginseng (Ren Shen), rootstock of
Radix Ophiopogonis (Mai Dong), and dry ripe fruit of
Fructus Schisandrae (Wu Wei Zi), which is recorded in the Yi Xue Qi Yuan, compiled by Yuan-su Zhang. It was mainly used for treating heart failure, myocardial ischemia, coronary heart disease, arrhythmia, myocarditis, and sick sinus syndrome [
16‐
18]. We have earlier shown that SMS treatment alleviated myocardial damage and inhibited myocardial fibrosis in diabetic rats. SMS has also been proven to suppress cardiomyocyte apoptosis; however, its upstream mechanism is still unclear [
19,
20]. Therefore, in this study, our aim was to explore the mechanisms underlying SMS activity with respect to cardiomyocyte apoptosis and provide new scientific evidence in favor of using traditional Chinese medicine to prevent DCM related damage.