5-Oxoproline prevents doxorubicin-induced cardiotoxicity and tumor growth
Background: Doxorubicin (DOX), a classical chemotherapeutic agent, faces significant limitations because of its well-documented risk of inducing cardiotoxicity. Effective prevention of DOX-induced cardiotoxicity is urgently needed. Given that alterations in metabolic pathways have been observed in b...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-09-01
|
| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725002666 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849226993385603072 |
|---|---|
| author | Xinning Guo Meng Jiang Zhengyu Tao Huijuan Dai Chen Wu Yinan Wang Zi Wang Xiaoning Wang Zhixuan Zhang Kun Qian Shanshan Zeng Yihua Bei Jun Pu |
| author_facet | Xinning Guo Meng Jiang Zhengyu Tao Huijuan Dai Chen Wu Yinan Wang Zi Wang Xiaoning Wang Zhixuan Zhang Kun Qian Shanshan Zeng Yihua Bei Jun Pu |
| author_sort | Xinning Guo |
| collection | DOAJ |
| description | Background: Doxorubicin (DOX), a classical chemotherapeutic agent, faces significant limitations because of its well-documented risk of inducing cardiotoxicity. Effective prevention of DOX-induced cardiotoxicity is urgently needed. Given that alterations in metabolic pathways have been observed in both cardiovascular diseases and cancer, targeting specific metabolic pathways may offer dual benefits by mitigating DOX-induced cardiotoxicity while simultaneously enhancing its antitumor efficacy. Objectives: This study sought to explore the characteristic metabolic alterations associated with early DOX-induced cardiotoxicity and identify a therapeutic target that simultaneously inhibits cancer and protects the myocardium. Methods: Metabolomic and transcriptomic analyses were performed on heart tissues from murine models of DOX-induced cardiotoxicity to identify the most significantly altered metabolic pathway. The most altered metabolite involved in the candidate pathway was chosen and verified in both mice and humans. The protective effects of the chosen metabolite against DOX-induced cardiotoxicity and its antitumor effects were evaluated. Potential mechanisms were explored using C57BL/6J mice, OPLAH global knockout mice, BALB/c nude mice and NSG mice. Results: The glutathione metabolic pathway was identified as the most altered pathway in heart tissues with DOX-induced cardiotoxicity. The 5-oxoproline/OPLAH (5-oxoprolinase) axis was the most critical node. Downregulation of 5-oxoproline was observed in serum samples from both humans and mice. Exogenous 5-oxoproline supplementation effectively restored myocardial 5-oxoproline levels, subsequently mitigating DOX-induced cardiac dysfunction. Interestingly, we observed an additional inhibitory effect of 5-oxoproline on tumor proliferation in tumor-bearing mice treated with DOX. Mechanistically, 5-oxoproline exerts its cardioprotective effects by restoring glutathione metabolic homeostasis through the modulation of its downstream enzyme OPLAH while simultaneously suppressing tumor proliferation by inhibiting its upstream enzyme, gamma-glutamyl cyclotransferase (GGCT). Conclusions: This study reveals a previously unrecognized dual role of 5-oxoproline, which functions both as an early biomarker for DOX-induced cardiotoxicity detection and as a therapeutic target that simultaneously inhibits cancer growth and protects the myocardium. |
| format | Article |
| id | doaj-art-2ec3db6bcd424f1d94b5631329470b48 |
| institution | Kabale University |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-2ec3db6bcd424f1d94b5631329470b482025-08-24T05:12:29ZengElsevierRedox Biology2213-23172025-09-018510375310.1016/j.redox.2025.1037535-Oxoproline prevents doxorubicin-induced cardiotoxicity and tumor growthXinning Guo0Meng Jiang1Zhengyu Tao2Huijuan Dai3Chen Wu4Yinan Wang5Zi Wang6Xiaoning Wang7Zhixuan Zhang8Kun Qian9Shanshan Zeng10Yihua Bei11Jun Pu12Department of Cardiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, ChinaDepartment of Cardiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China; Corresponding author. Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Shanghai, 200127, China.Department of Cardiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, ChinaDepartment of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, ChinaDepartment of Cardiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, ChinaDepartment of Cardiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, ChinaDepartment of Cardiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, ChinaDepartment of Cardiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, ChinaDepartment of Cardiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, ChinaSchool of Biomedical Engineering, Institute of Medical Robotics and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, ChinaSchool of Biomedical Engineering, Institute of Medical Robotics and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, ChinaCardiac Regeneration and Aging Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Sciences, Shanghai University, Shanghai, 200444, China; Corresponding author. Cardiac Regeneration and Aging Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Sciences, Shanghai University, Shanghai, 200444, China.Department of Cardiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China; Corresponding author. Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Shanghai 200127, China.Background: Doxorubicin (DOX), a classical chemotherapeutic agent, faces significant limitations because of its well-documented risk of inducing cardiotoxicity. Effective prevention of DOX-induced cardiotoxicity is urgently needed. Given that alterations in metabolic pathways have been observed in both cardiovascular diseases and cancer, targeting specific metabolic pathways may offer dual benefits by mitigating DOX-induced cardiotoxicity while simultaneously enhancing its antitumor efficacy. Objectives: This study sought to explore the characteristic metabolic alterations associated with early DOX-induced cardiotoxicity and identify a therapeutic target that simultaneously inhibits cancer and protects the myocardium. Methods: Metabolomic and transcriptomic analyses were performed on heart tissues from murine models of DOX-induced cardiotoxicity to identify the most significantly altered metabolic pathway. The most altered metabolite involved in the candidate pathway was chosen and verified in both mice and humans. The protective effects of the chosen metabolite against DOX-induced cardiotoxicity and its antitumor effects were evaluated. Potential mechanisms were explored using C57BL/6J mice, OPLAH global knockout mice, BALB/c nude mice and NSG mice. Results: The glutathione metabolic pathway was identified as the most altered pathway in heart tissues with DOX-induced cardiotoxicity. The 5-oxoproline/OPLAH (5-oxoprolinase) axis was the most critical node. Downregulation of 5-oxoproline was observed in serum samples from both humans and mice. Exogenous 5-oxoproline supplementation effectively restored myocardial 5-oxoproline levels, subsequently mitigating DOX-induced cardiac dysfunction. Interestingly, we observed an additional inhibitory effect of 5-oxoproline on tumor proliferation in tumor-bearing mice treated with DOX. Mechanistically, 5-oxoproline exerts its cardioprotective effects by restoring glutathione metabolic homeostasis through the modulation of its downstream enzyme OPLAH while simultaneously suppressing tumor proliferation by inhibiting its upstream enzyme, gamma-glutamyl cyclotransferase (GGCT). Conclusions: This study reveals a previously unrecognized dual role of 5-oxoproline, which functions both as an early biomarker for DOX-induced cardiotoxicity detection and as a therapeutic target that simultaneously inhibits cancer growth and protects the myocardium.http://www.sciencedirect.com/science/article/pii/S2213231725002666Cardio-oncology5-oxoprolineCardiotoxicityHeart failureDoxorubicinBreast cancer |
| spellingShingle | Xinning Guo Meng Jiang Zhengyu Tao Huijuan Dai Chen Wu Yinan Wang Zi Wang Xiaoning Wang Zhixuan Zhang Kun Qian Shanshan Zeng Yihua Bei Jun Pu 5-Oxoproline prevents doxorubicin-induced cardiotoxicity and tumor growth Redox Biology Cardio-oncology 5-oxoproline Cardiotoxicity Heart failure Doxorubicin Breast cancer |
| title | 5-Oxoproline prevents doxorubicin-induced cardiotoxicity and tumor growth |
| title_full | 5-Oxoproline prevents doxorubicin-induced cardiotoxicity and tumor growth |
| title_fullStr | 5-Oxoproline prevents doxorubicin-induced cardiotoxicity and tumor growth |
| title_full_unstemmed | 5-Oxoproline prevents doxorubicin-induced cardiotoxicity and tumor growth |
| title_short | 5-Oxoproline prevents doxorubicin-induced cardiotoxicity and tumor growth |
| title_sort | 5 oxoproline prevents doxorubicin induced cardiotoxicity and tumor growth |
| topic | Cardio-oncology 5-oxoproline Cardiotoxicity Heart failure Doxorubicin Breast cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2213231725002666 |
| work_keys_str_mv | AT xinningguo 5oxoprolinepreventsdoxorubicininducedcardiotoxicityandtumorgrowth AT mengjiang 5oxoprolinepreventsdoxorubicininducedcardiotoxicityandtumorgrowth AT zhengyutao 5oxoprolinepreventsdoxorubicininducedcardiotoxicityandtumorgrowth AT huijuandai 5oxoprolinepreventsdoxorubicininducedcardiotoxicityandtumorgrowth AT chenwu 5oxoprolinepreventsdoxorubicininducedcardiotoxicityandtumorgrowth AT yinanwang 5oxoprolinepreventsdoxorubicininducedcardiotoxicityandtumorgrowth AT ziwang 5oxoprolinepreventsdoxorubicininducedcardiotoxicityandtumorgrowth AT xiaoningwang 5oxoprolinepreventsdoxorubicininducedcardiotoxicityandtumorgrowth AT zhixuanzhang 5oxoprolinepreventsdoxorubicininducedcardiotoxicityandtumorgrowth AT kunqian 5oxoprolinepreventsdoxorubicininducedcardiotoxicityandtumorgrowth AT shanshanzeng 5oxoprolinepreventsdoxorubicininducedcardiotoxicityandtumorgrowth AT yihuabei 5oxoprolinepreventsdoxorubicininducedcardiotoxicityandtumorgrowth AT junpu 5oxoprolinepreventsdoxorubicininducedcardiotoxicityandtumorgrowth |