Clinical use of the anti-cancer drug doxorubicin (DOX) is largely limited due to its severe cardiotoxicity. Dysregulation of autophagy is implicated in DOX-induced cardiotoxicity (DIC). Prior studies have indicated that Beclin1 and lysosomal-associated membrane proteins-1 (LAMP1) are critical mediators of autophagy. In this work, by assessing autophagic flux in a DOX-stimulated H9C2 model, we observed autolysosome accumulation caused by interruption of autolysosome degradation. Tanshinone IIA (TSA) is a well-known small molecule that exerts impressive cardioprotective effects on heart failure. Here, we investigated the regulation of TSA in DOX-treated zebrafish, mice, and H9C2 models. Results demonstrated that TSA remarkably improved heart function and reversed pathological changes in vivo, while TSA restored autophagic flux by promoting autolysosome degradation and autophagosome formation. Further experiments demonstrated that these effects were mediated through upregulation of Beclin1 and LAMP1. The mTOR agonist MHY1485 was shown to abrogate the effect of TSA via the UNC-51-like kinase 1 (ULK1)-Beclin1/TFEB-LAMP1 signaling pathway in vitro, demonstrating that TSA protects against DIC by promoting autophagy via the Beclin1/LAMP1 signaling pathway. We further employed a U87 model to assess whether TSA would compromise the antitumor activity of DOX. Intriguingly, the co-treatment of TSA was able to synergistically inhibit proliferative activity. Collectively, in this study we uncover the novel insight that TSA is able to reduce the cardiotoxicity of DOX without compromising antitumor activity.

Doxorubicin (DOX) is an anthracycline chemotherapy drug, which is indispensable in antitumor therapy. However, its subsequent induction of cardiovascular disease (CVD) has become the primary cause of mortality in cancer survivors. Accumulating evidence has demonstrated that cardiac mitochondrial bioenergetics changes have become a significant marker for doxorubicin‐induced cardiotoxicity (DIC). Here, we mainly summarize the related mechanisms of DOX‐induced cardiac mitochondrial bioenergetics disorders reported in recent years, including mitochondrial substrate metabolism, the mitochondrial respiratory chain, myocardial ATP storage and utilization, and other mechanisms affecting mitochondrial bioenergetics. In addition, intervention for DOX‐induced cardiac mitochondrial bioenergetics disorders using chemical drugs and traditional herbal medicine is also summarized, which will provide a comprehensive process to study and develop more appropriate therapeutic strategies for DIC.

Doxorubicin (DOX), the anthracycline chemotherapeutic agent, is widely used for the treatment of various cancers. However, its clinical application is compromised by dose‐dependent and fatal cardiotoxicity. This study is aimed at investigating the cardioprotective effects of Qishen granule (QSG) and the specific mechanism by which QSG alleviates DOX‐induced cardiotoxicity (DIC) and providing an alternative for the treatment of DIC. We first evaluated the cardioprotective effects of QSG in a DIC mouse model, and the obtained results showed that QSG significantly protected against DOX‐induced myocardial structural and functional damage, mitochondrial oxidative damage, and apoptosis. Subsequently, after a comprehensive understanding of the specific roles and recent developments of p53‐mediated mitochondrial quality control mechanisms in DIC, we investigated whether QSG acted on MDM2 to regulate the activity of p53 and downstream mitophagy and mitochondrial biogenesis. The in vivo results showed that DOX inhibited mitochondrial biogenesis and blocked mitophagy in the mouse myocardium, while QSG reversed these effects. Mechanistically, we combined nutlin‐3, which inhibits the binding of p53 and MDM2, with DOX and QSG and evaluated their influence on mitophagy and mitochondrial biogenesis in H9C2 cardiomyocytes. The obtained results showed that both DOX and nutlin‐3 substantially inhibited mitophagy and mitochondrial biogenesis and induced mitochondrial oxidative damage and apoptosis, which could be partially recovered by QSG. Importantly, the immunoprecipitation results showed that QSG promoted the binding of MDM2 to p53, thus decreasing the level of p53 protein and the binding of p53 to Parkin. Collectively, QSG could promote the degradation of p53 by enhancing the binding of MDM2 to the p53 protein, resulting in the reduced binding of p53 to the Parkin protein, thus improving Parkin‐mediated mitophagy. Increased degradation of p53 protein by QSG simultaneously enhanced mitochondrial biogenesis mediated by PGC‐1α. Ultimately, QSG relieved DOX‐induced mitochondrial oxidative damage and apoptosis by coordinating mitophagy and mitochondrial biogenesis.

BACKGROUND: Anthracycline-induced cardiotoxicity (AIC) limits life-saving chemotherapy and is driven by early metabolic remodeling. The nuclear receptor ERRα (estrogen-related receptor α) is a master regulator of cardiac energy metabolism, but the temporal dynamics of its downregulation, its causal role in AIC pathogenesis, and whether it can be pharmacologically activated to confer protection remain undefined. METHODS: We performed temporal protein analysis in a porcine AIC model. Using cardiomyocyte-specificgain- and loss-of-function mouse models, we assessed the causal role of ERRα. Mechanistic studies included ChIP-qPCR, reporter assays, and microscale thermophoresis to investigate the natural compound formononetin. Human breast cancer patient-derived organoids were used to evaluate anticancer activity. RESULTS: ERRα expression was selectively downregulated in AIC pig hearts and cardiac tissue from chemotherapy-treated patients. Temporal analysis in pigs revealed that ERRα reduction occurred at the subclinical (6-week) stage, preceding overt cardiac dysfunction. Cardiomyocyte-specific ERRα overexpression activated mitochondrial gene programs, enhanced fatty acid oxidation, and preserved systolic function after doxorubicin challenge, whereas ERRα knockdown exacerbated bioenergetic failure and cardiac dysfunction. Through drug screening, we identified formononetin as a potent and selective ERRα agonist. Formononetin enhanced ERRα transcriptional activity, improved mitochondrial metabolism, and protected against AIC in both murine and porcine models. Mechanistically, ChIP-qPCR demonstrated increased ERRα occupancy at target gene promoters, and microscale thermophoresis confirmed direct binding of formononetin to the ERRα/PGC-1α (peroxisome proliferator-activated receptor γ coactivator-1α) complex, indicating allosteric stabilization. Finally, in human breast cancer patient-derived organoids, formononetin alone reduced viability and proliferation, and combined with doxorubicin further enhanced antitumor efficacy. CONCLUSIONS: ERRα downregulation is a causal early event in the pathogenesis of AIC. Formononetin acts as a first-in-class selective ERRα activator that improves cardiac metabolism and function while retaining anticancer activity, supporting its potential as a dual-action cardioprotective agent during anthracycline therapy.