Chamber–Specific Molecular Profiling of Doxorubicin-Induced Cardiotoxicity via Integrated Multi-Omics Analysis
6 affiliations
- 1Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- 2Institute of Cardio-Oncology, Fudan University (in preparation), Shanghai 200032, China
- 3State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- 4Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
- 5Department of Echocardiography, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- 6Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, 180 Fenglin Road, Shanghai 200032, China
Abstract
Background: Doxorubicin (Dox) induces dose-dependent Dox–induced cardiotoxicity (DIC), but the chamber-specific molecular mechanisms remain unclear, as traditional analyses rely on whole-heart homogenates. Methods: We established rat acute single–dose and chronic cumulative–dose DIC models, and separated left atrium (L–atrium) and left ventricle (L–ventricle) tissues for subsequent detection. Liquid chromatography–tandem mass spectrometry (LC–MS/MS) was used to quantify regional Dox tissue and serum concentrations. Histological HE and Masson’s staining were used to evaluate myocardial structural injury and collagen deposition. Integrated chamber-specific bulk proteomics, phosphoproteomics, and untargeted metabolomics were applied to systematically compare molecular perturbations between the L-atrium and L-ventricle. Two–way factorial statistical decomposition coupled with functional enrichment analysis was subsequently performed to identify both shared and chamber-specific molecular signatures. Results: Histological staining confirmed pronounced obvious myocardial fibrosis in both the L–atrium and L–ventricle under chronic Dox exposure. LC–MS/MS revealed prominent L–atrium–predominant Dox accumulation in the acute model, while inter–chamber drug distribution differences vanished after long–term repeated administration. Proteomic and metabolomic responses exhibited high inter–chamber consistency (r = 0.864 and r = 0.911, respectively). In contrast, the phosphoproteome was the dominant regulatory layer driving chamber divergence. A total of 14 core phosphosites with significant tissue–drug interaction effects were identified as key molecular switches. Conclusions: Our findings reveal preferential atrial Dox accumulation and distinct atrial phosphorylation remodeling following Dox exposure. The identified differential phosphosites serve as promising candidate targets for chamber-specific cardioprotection against DIC, pending further functional validation.
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BibTeX
@article{zhang2026chamberspecific,
title = {{Chamber–Specific Molecular Profiling of Doxorubicin-Induced Cardiotoxicity via Integrated Multi-Omics Analysis}},
author = {Jian Zhang and Yue Sun and Xiaozhen He and Yerui Zhang and Shijun Wang and Leilei Cheng},
journal = {Metabolites},
year = {2026},
month = oct,
doi = {10.3390/metabo16100746},
url = {https://www.mdpi.com/2218-1989/16/10/746},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Chamber–Specific Molecular Profiling of Doxorubicin-Induced Cardiotoxicity via Integrated Multi-Omics Analysis
AU - Jian Zhang
AU - Yue Sun
AU - Xiaozhen He
AU - Yerui Zhang
AU - Shijun Wang
AU - Leilei Cheng
PY - 2026
DA - 2026/10/01
JO - Metabolites
DO - 10.3390/metabo16100746
UR - https://www.mdpi.com/2218-1989/16/10/746
AB - Background: Doxorubicin (Dox) induces dose-dependent Dox–induced cardiotoxicity (DIC), but the chamber-specific molecular mechanisms remain unclear, as traditional analyses rely on whole-heart homogenates. Methods: We established rat acute single–dose and chronic cumulative–dose DIC models, and separated left atrium (L–atrium) and left ventricle (L–ventricle) tissues for subsequent detection. Liquid chromatography–tandem mass spectrometry (LC–MS/MS) was used to quantify regional Dox tissue and serum concentrations. Histological HE and Masson’s staining were used to evaluate myocardial structural injury and collagen deposition. Integrated chamber-specific bulk proteomics, phosphoproteomics, and untargeted metabolomics were applied to systematically compare molecular perturbations between the L-atrium and L-ventricle. Two–way factorial statistical decomposition coupled with functional enrichment analysis was subsequently performed to identify both shared and chamber-specific molecular signatures. Results: Histological staining confirmed pronounced obvious myocardial fibrosis in both the L–atrium and L–ventricle under chronic Dox exposure. LC–MS/MS revealed prominent L–atrium–predominant Dox accumulation in the acute model, while inter–chamber drug distribution differences vanished after long–term repeated administration. Proteomic and metabolomic responses exhibited high inter–chamber consistency (r = 0.864 and r = 0.911, respectively). In contrast, the phosphoproteome was the dominant regulatory layer driving chamber divergence. A total of 14 core phosphosites with significant tissue–drug interaction effects were identified as key molecular switches. Conclusions: Our findings reveal preferential atrial Dox accumulation and distinct atrial phosphorylation remodeling following Dox exposure. The identified differential phosphosites serve as promising candidate targets for chamber-specific cardioprotection against DIC, pending further functional validation.
SN - 2218-1989
ER -