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Article

Multifaceted Cardioprotective Potential of Reduced Glutathione Against Doxorubicin-Induced Cardiotoxicity via Modulating Inflammation–Oxidative Stress Axis

by
Amr Negm
1,*,
Ezat A. Mersal
2,
Amal F. Dawood
3,
Amira O. Abd El-Azim
4,
Omar Hasan
2,
Rayan Alaqidi
2,
Ahmed Alotaibi
2,
Mohammed Alshahrani
2,
Abdullah Alheraiz
2 and
Tamer M. Shawky
5
1
Department of Chemistry, College of Science, King Faisal University, Al-Ahsa 31982, Saudi Arabia
2
Department of Basic Medical Sciences, Vision Colleges, Riyadh 13226, Saudi Arabia
3
Department of Basic Medical Sciences, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
4
Zoology Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt
5
Department of Anatomy and Embryology, Faculty of Medicine, Cairo University, Giza 12613, Egypt
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(7), 3201; https://doi.org/10.3390/ijms26073201
Submission received: 18 February 2025 / Revised: 14 March 2025 / Accepted: 26 March 2025 / Published: 30 March 2025
(This article belongs to the Special Issue Cardiovascular Disease: Molecular Advances on Pathophysiology and Therapies)
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Abstract

Doxorubicin (DOX) is a potent chemotherapeutic agent used to treat many types of cancer. Its use is limited because of the reported accompanied cardiotoxicity, which is driven by oxidative stress and inflammation. Herin, we explored the cardioprotective impact of reduced glutathione (GSH) against DOX-induced cardiac damage in a mice model and highlighted the dynamic interplay between pro-inflammatory and antioxidant mechanisms, with tissue damage markers and oxidative byproducts. Mice were divided into four groups and administered DOX, GSH, or a combination, and the outcomes were compared to untreated controls. DOX administration caused significant mortality, weight loss, elevated serum markers of cardiac injury (CK-MB and LDH), oxidative stress (MDA and iron), pro-inflammatory cytokines (IL-6, IL-17, and IL-23), and upregulated pro-inflammatory gene expression of STAT-3 and NFκB as well as downregulated gene expression of NRF-2 and HO-1. Histological analysis showed myocardial fibrosis, vacuolization, and apoptosis, as confirmed by a TUNEL assay. Meanwhile, treatment with GSH improved survival rate, attenuated weight loss, and restored cardiac function markers. Furthermore, GSH suppressed oxidative stress and inflammation, modulated gene expression, and declined histopathological damage. These findings demonstrated the multifaceted cardioprotection of GSH through the restoration of redox homeostasis and modulation of the pro- and anti-inflammatory responses. GSH supplementation emerges as a promising adjunct therapy to mitigate DOX-induced cardiotoxicity, offering a strategy to improve cardiac health in cancer patients undergoing doxorubicin chemotherapy.
Keywords: doxorubicin-induced cardiotoxicity; glutathione (GSH); oxidative stress; inflammation; cardioprotective mechanisms doxorubicin-induced cardiotoxicity; glutathione (GSH); oxidative stress; inflammation; cardioprotective mechanisms

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MDPI and ACS Style

Negm, A.; Mersal, E.A.; Dawood, A.F.; Abd El-Azim, A.O.; Hasan, O.; Alaqidi, R.; Alotaibi, A.; Alshahrani, M.; Alheraiz, A.; Shawky, T.M. Multifaceted Cardioprotective Potential of Reduced Glutathione Against Doxorubicin-Induced Cardiotoxicity via Modulating Inflammation–Oxidative Stress Axis. Int. J. Mol. Sci. 2025, 26, 3201. https://doi.org/10.3390/ijms26073201

AMA Style

Negm A, Mersal EA, Dawood AF, Abd El-Azim AO, Hasan O, Alaqidi R, Alotaibi A, Alshahrani M, Alheraiz A, Shawky TM. Multifaceted Cardioprotective Potential of Reduced Glutathione Against Doxorubicin-Induced Cardiotoxicity via Modulating Inflammation–Oxidative Stress Axis. International Journal of Molecular Sciences. 2025; 26(7):3201. https://doi.org/10.3390/ijms26073201

Chicago/Turabian Style

Negm, Amr, Ezat A. Mersal, Amal F. Dawood, Amira O. Abd El-Azim, Omar Hasan, Rayan Alaqidi, Ahmed Alotaibi, Mohammed Alshahrani, Abdullah Alheraiz, and Tamer M. Shawky. 2025. "Multifaceted Cardioprotective Potential of Reduced Glutathione Against Doxorubicin-Induced Cardiotoxicity via Modulating Inflammation–Oxidative Stress Axis" International Journal of Molecular Sciences 26, no. 7: 3201. https://doi.org/10.3390/ijms26073201

APA Style

Negm, A., Mersal, E. A., Dawood, A. F., Abd El-Azim, A. O., Hasan, O., Alaqidi, R., Alotaibi, A., Alshahrani, M., Alheraiz, A., & Shawky, T. M. (2025). Multifaceted Cardioprotective Potential of Reduced Glutathione Against Doxorubicin-Induced Cardiotoxicity via Modulating Inflammation–Oxidative Stress Axis. International Journal of Molecular Sciences, 26(7), 3201. https://doi.org/10.3390/ijms26073201

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