Integrated computational biology approaches provide insights into the potential mechanisms underlying arrhythmias induced by anthraquinone-related antitumor drugs

Despite the significant cardiac toxicity and arrhythmia-inducing potential of anthraquinone-related antitumor drugs (including anthracyclines and anthracenediones) in clinical practice, the underlying common systemic molecular mechanisms remain unknown. Therefore, this study aims to systematically elucidate the multi-target and multi-pathway arrhythmogenic mechanisms of seven representative drugs, with the expectation of providing theoretical support for safe clinical use and the development of related toxicity intervention strategies. This study first employed network toxicology techniques to screen out potential arrhythmogenic targets of seven representative drugs from databases such as PubChem, Novo Pro, and SwissTargetPrediction. Subsequently, based on the STRING database and with the aid of Cytoscape 3.10.1, protein-protein interaction networks and a multi-dimensional “arrhythmia-drug-target” network were constructed. Further, GO and KEGG enrichment analyses were conducted to explain the toxicity-related biological processes and key signaling pathways, and their roles in immune infiltration were explored. Finally, molecular docking was used to assess the potential binding interactions between drugs and core targets. Two drug–SRC complexes were selected for further molecular dynamics simulations to evaluate the stability. Combined with ADMET assessment, these computational analyses provide a comprehensive and hypothesis-generating assessment of the potential toxicological profiles and underlying mechanisms of anthraquinone-related antitumor drugs. Through network pharmacology, 195 potential toxicity targets (such as AKT1, SRC, TNF, TP53) were identified, and they were significantly enriched in key signaling pathways such as PI3K-Akt and MicroRNAs in cancer. Immune infiltration analysis further suggested that this process might be related to the regulation of immune cells such as Mast cells activated, T cells CD8 and B cells memory. Molecular docking suggested potential interactions between the drugs and the core target, while dynamic simulations further evaluated the stability of the SRC complex of the two selected drugs. Finally, ADMET predictions indicated that Mitoxantrone and Losoxantrone might block the cardiac hERG potassium channel, prolong the QT interval, and thereby may contribute to arrhythmia. This study provides insights into the potential mechanisms by which anthraquinone-related antitumor drugs induce arrhythmias.