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  3. Identification of cardiotoxic targets of doxorubicin via network toxicology and development of exosome-based delivery system for osteosarcoma therapy

Identification of cardiotoxic targets of doxorubicin via network toxicology and development of exosome-based delivery system for osteosarcoma therapy

  • Int Immunopharmacol. 2025 Aug 28:161:115011. doi: 10.1016/j.intimp.2025.115011.
Jun Xu 1,  Sihan Zhou 2,  Yuanyuan Xu 2,  Bin Shen 2,  Xiaoqing Zhang 2,  Jun Guo 3,  Jingjian Dong 4,  Lili Shi 5,  Xiaohong Jiang 6
Affiliations

Affiliations

  • 1 Department of Emergency, Affiliated Hospital of Jiaxing University/The First Hospital of Jiaxing, Zhejiang Province, China.
  • 2 College of Medicine, Jiaxing University, Jiaxing, Zhejiang, China.
  • 3 College of Food Science and Engineering, Tianjin University of Science and Technology, Tianjin, China.
  • 4 College of Medicine, Jiaxing University, Jiaxing, Zhejiang, China. Electronic address: jingjianwy@163.com.
  • 5 College of Medicine, Jiaxing University, Jiaxing, Zhejiang, China. Electronic address: wssll0@126.com.
  • 6 College of Medicine, Jiaxing University, Jiaxing, Zhejiang, China. Electronic address: 276015487@qq.com.
PMID: 40466611 DOI: 10.1016/j.intimp.2025.115011
Abstract

Osteosarcoma (OS) is an aggressive bone Cancer with a poor prognosis, particularly in cases involving metastasis. While doxorubicin (ADM) is effective for OS treatment, its use is hindered by severe cardiotoxicity. This study aimed to investigate the molecular mechanisms underlying ADM-induced cardiac injury and develop a novel strategy to reduce its toxicity, focusing on exosome-mediated drug delivery. Network toxicology and molecular docking techniques were used to identify the key molecular targets involved in ADM-induced cardiac injury. A target database was constructed from public databases (ChEMBL, STITCH, Swiss Target Prediction, GeneCards, OMIM, and TTD), and Venn diagram analysis was performed to identify the shared targets between ADM and cardiac injury-related genes. A regulatory network was constructed, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses to gain insights into the biological processes involved. Additionally, exosomes were isolated from human osteosarcoma MG-63 cells and loaded with ADM via electroporation. The therapeutic efficacy and toxicity of exosome-encapsulated ADM (HOC-Exos@ADM) were evaluated using in vitro and in vivo models. Network toxicology analysis identified 27 shared targets between ADM and cardiac injury, including key genes such as Akt1, TP53, ESR1, and HIF1A. These genes are involved in Apoptosis, oxidative stress, and inflammation, all of which contribute to cardiac damage. The exosome-mediated delivery improved drug uptake, increased Apoptosis in OS cells. In Akt1 signaling, decreased Akt1 led to cardiomyocyte damage via GSK - 3β and mTOR pathways. Meanwhile, exhibited a safer profile in animal models. These results suggest that exosome-based delivery can reduce ADM-induced cardiotoxicity and enhance clinical outcomes for patients with OS.

Keywords

Doxorubicin; Exosome; Network toxicology; Osteosarcoma.

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