Heart failure is a tricky clinical syndrome caused by structural and functional damage to the heart in the end stage of cardiovascular disease (Greene et al., 2023). Globally, 19.05 million people will have already died from cardiovascular disease in 2020, an increase of 18.71% from a decade ago, with heart failure and sudden cardiac death mainly caused by ischemic heart disease (Ray et al., 2019; Frantz et al., 2022; Tsao et al., 2023). IHF accounted for 49.4% of all hospitalized heart failure patients in China (Zhang and Zhang, 2015); it also accounted for the highest proportion of heart failure causes worldwide, at 26.5% (Bragazzi et al., 2021). In particular, the rate of heart failure in patients readmitted within 30 days of myocardial infarction was 16.7%, and the risk of death or hospitalization for heart failure within 12–22 months was 12%–17% (J. Li et al., 2019; Harrington et al., 2022). Although thrombolysis, hemodialysis, and neuroendocrine inhibitors can improve patients' myocardial blood supply, the overall mortality rate of heart failure patients is still 21.6%, of which the 5-year rate is as low as 25% in hospitalized patients (Jenča et al., 2021; Sandoval et al., 2022). Cardiomyocyte necrosis and apoptosis due to ischemia and hypoxia in the infarcted area have long been thought to be the key to ventricular remodeling and cardiac decompensation (Bai et al., 2023). Modern medicine has explored the mechanisms of cardiomyocyte death in depth and found that ferroptosis, a mode of cell death caused by iron-catalyzed ROS oxidation of lipids, also plays a vital role in cardiomyocyte death after myocardial infarction (Jiang et al., 2023). Therefore, inhibition of CA and ferroptosis may be an effective treatment of IHF, and related studies are essential for clinical translation.

TCM has apparent advantages in treating IHF, which can comprehensively improve symptoms, is gentle and has no side effects, and is widely recognized for combining with Western medicine to form a treatment model that provides safe and effective treatment (J. Chen et al., 2023; Y. Yang et al., 2023). Studies in Chinese medicine have determined that qi deficiency and blood stasis are the basic TCM patterns of IHF (Zhou et al., 2019; Hu et al., 2021). Therefore, insufficiency of heart qi will seriously affect blood circulation, leading to an imbalance of yin and yang, producing clinical manifestations such as stasis and edema and triggering IHF (Leung et al., 2021; Pan et al., 2023). Through years of clinical practice, the nationally renowned TCM expert and Qihuang scholar, Professor Mao Jingyuan, found that the conventional Shengmai Powder had large dosages and inadequate qi reinforcement and diuresis effects. Adhering to TCM principles, he refined the formula, removing medicinals that might deplete vital energy and adding qi-reinforcing and diuretic herbs. Optimized New Shengmai Powder (ONSMP) significantly enhanced the overall qi reinforcement, blood activation, and diuresis effects (Wang et al., 2014; Wu, 2017). In the theoretical framework of TCM, the herbs in ONSMP each have distinct therapeutic effects: the primary herb Astragalus mongholicus Bunge can fortify the body's "qi" and promote urination; herbs Codonopsis pilosula (Franch.) Nannf., Eleutherococcus senticosus (Rupr. & Maxim.) Maxim., and Salvia miltiorrhiza Bunge aim to tonify qi and stimulate blood circulation; supplementary herbs Trionyx sinensis Wiegmann and Poria cocos (Schw.) Wolf can enhance blood flow and aid in water retention, while Lepidium apetalum Willd primarily focuses on dispersing lung qi and promoting urination; Citrus × aurantium L. can assist in bolstering qi, and Ophiopogon japonicus (Thunb.) Ker Gawl. nourishes the blood, prevents yin depletion, and restores the pulse (Wu, 2017). Clinical studies have shown that ONSMP can not only significantly improve the LVEF of patients with heart failure, effectively relieving symptoms such as shortness of breath, fatigue, and facial and limb swelling, but also significantly increase patients' walking distance in the 6 min walk test, enhancing their physical fitness and daily activity abilities. It is worth mentioning that ONSMP's treatment process is safe and reliable, with no significant adverse reactions or side effects (Wang et al., 2015; Wu, 2017). Previous experimental studies have shown that ONSMP exhibits significant anti-apoptosis and anti-ferroptosis effects in treating heart failure. It can regulate the calcium concentration and inhibit the generation of reactive oxygen species in cardiomyocytes of IHF rats, thus strengthening myocardial contraction while reducing myocardial damage caused by cardiomyocyte apoptosis and ferroptosis (Hou et al., 2023). In addition, based on its anti-cardiomyocyte death and anti-myocardial fibrosis effects, ONSMP significantly improved myocardial remodeling in IHF heart failure rats (S. Wang et al., 2023; Zhang et al., 2024). In the doxorubicin-induced heart failure model, ONSMP improved malondialdehyde levels and superoxide dismutase activity, which protected cardiomyocytes and increased survival and prolonged forceful swimming time in mice (Pang et al., 2012). Given that doxorubicin causes cardiac iron overload, downregulation of glutathione peroxidase 4 expression, and reactive oxygen species accumulation, which promotes intracellular lipid peroxidation and the production of harmful substances such as malondialdehyde and ultimately triggers ferroptosis (Fang et al., 2019; Hou et al., 2021). These findings further support the anti-apoptotic and anti-ferroptosis properties of ONSMP.

ONSMP has crucial clinical value and application prospects in treating ischemic heart disease. However, studying its complex composition and multi-target mechanism of action is highly challenging. Network pharmacology of TCM is a branch of systems biology that studies the interactions of TCM components with disease targets to reveal the pharmacological effects and potential therapeutic value of TCM. It is also an essential research tool for the modernization and globalization of TCM (Zhao et al., 2023). Given that the specific mechanisms of how ONSMP counters CA and ferroptosis in IHF remain unclear, this study first established a rat model of IHF by surgically inducing acute myocardial infarction. Subsequently, we conducted pharmacodynamic studies on diseased rats treated with ONSMP. To further explore its mechanisms, we employed bioinformatics analysis techniques for in-depth exploration and verified relevant signaling pathways and targets through in vivo experiments. The core objective of this study is to elucidate how ONSMP inhibits cell apoptosis and ferroptosis in IHF, aiming to lay a solid theoretical foundation for the clinical application of ONSMP.