Doxorubicin (DOX) has been widely used in the treatment of many solid tumors and hematological tumors. However, the widespread use of DOX was restricted due to their cardiotoxicity, which threatened anti-tumor treatment and patients’ quality of life (Carvalho et al., 2014; Ranjbarvaziri et al., 2021). While the exact mechanisms of anthracycline induced cardiotoxicity have yet to be elucidated, multiple studies have identified oxidative stress and mitochondrial metabolism dysfunction as the main causes of cardiotoxicity (Koleini et al., 2019). Hence, cardioprotective strategies based on the oxidative stress and mitochondrial metabolism are needed to alleviate cardiotoxicity.

Tongmai Yangxin (TMYX) Pill, a Chinese patent medicine composed of the ancient classic prescription Zhiguorice decoction and Shengmai powder, is widely used in clinical treatment of cardiovascular diseases. A large number of traditional Chinese medicine literature and clinical evidence indicate that TMYX has extensive protective effects on the heart, e.g. anti-ventricular remodeling (Wang, Y. et al., 2024), anti-inflammatory activity (Fan et al., 2021), anti-oxidative stress (Cui et al., 2018) et al. TMYX is composed of 11 Chinese herbs: Radix rehmanniae (Rehmannia glutinosa (Gaertn.) DC., Dihuang), Spatholobi caulis (Spatholobus suberectus Dunn [Fabaceae], Jixueteng), Radix ophiopogonis (Ophiopogon japonicus (Thunb.) Ker Gawl., Maidong), Glycyrrhiza (Glycyrrhiza glabra L. [Fabaceae], Gancao), Prepared fleeceflower root (Reynoutria multiflora (Thunb.) Moldenke [Polygonaceae], Zhiheshouwu), Balsamum peruvianum (Myroxylon balsamum (L.) Harms [Fabaceae], Ejiao), Fructus schisandrae chinensis (Schisandra chinensis (Turcz.) Baill. [Schisandraceae], Wuweizi), Radix Codonopsis (Codonopsis pilosula (Franch.) Nannf. [Campanulaceae], Dangsen), Vinegar tortoise shell (Phyllostachys edulis (Carrière) J.Houz. [Poaceae], Cuguijia), Jujube (Ziziphus jujuba Mill. [Rhamnaceae], Dazao), Cassia twig (Neolitsea cassia (L.) Kosterm. [Lauraceae], Guizhi). The potential synergistic effects among various herbs. For example, ramulus cinnamomi enhanced the absorption of four bioactive components: liquiritigenin, isoliquiritigenin, glycyrrhizic acid, and glycyrrhetinic acid (Fan et al., 2016).

TMYX possesses solid evidence-based medical support for its efficacy in treating coronary heart disease with angina pectoris and arrhythmia characterized by Qi and Yin deficiency syndrome (Liu et al., 2022; Wang et al., 2020). Our previous study showed that TMYX improved anti-oxidative stress ability and reduced the apoptosis of cardiomyocytes through Nrf 2/HO-1 and p38-MAPK pathway (Cui et al., 2018). Based on these data, we found that TMYX was promising as a candidate antidote for DOX cardiotoxicity.

N6-Methyladenosine (m6A), as the most abundant RNA modification in eukaryotes, could regulate the RNA splicing, stability and localization (Cui et al., 2022, 2025; Zhang et al., 2021). The novel reversible mRNA modifications have been highlighted and the demethylase ALKBH5 and FTO were discovered to be involved in dynamic m6A modification (Hengwei et al., 2022). However, the status of m6A modification and the potential regulatory mechanisms in DOX-induced chronic cardiotoxicity is remain unclear.

In present study, our research investigated the cardioprotection of TMYX on DOX-induced cardiotoxicity via ameliorating cardiomyocytes energy metabolism. The deepgoing mechanism by TMYX was further explored, providing a novel perspective on the role of Chinese medicine compounds in the treatment of DOX-induced chronic cardiotoxicity.