# RESEARCH HIGHLIGHTS-NYCU-Led Interdisciplinary Study Identifies Hesperetin as a Cardioprotective Agent That Preserves Doxorubicin’s Anti-Tumor Effect-National Yang Ming Chiao Tung University

**Source**: https://www.nycu.edu.tw/nycu/en/app/news/view?module=headnews&id=623&serno=4c047040-1cb4-4e4a-89f3-6947171a46d6
**Parent**: https://www.nycu.edu.tw/nycu/en/app/news/list?module=headnews&id=623

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[中文](https://www.nycu.edu.tw/nycu/ch/app/news/view?module=headnews&id=2994&serno=481d6a32-b25b-4b76-ae1f-7f024b795e36 "English to Chinese translation")

- Update Date：2025-10-27
- Units：Office of International Promotion and Outreach

NYCU-Led Interdisciplinary Study Identifies Hesperetin as a Cardioprotective Agent That Preserves Doxorubicin’s Anti-Tumor Effect

**Edited by Chance Lai**\
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An estimated 300,000 to 1.2 million cancer survivors worldwide who were treated with the chemotherapy drug Doxorubicin—nicknamed “Red Berry” for its deep red hue—experience varying degrees of chronic heart failure after overcoming cancer. In a groundbreaking interdisciplinary study, researchers from National Yang Ming Chiao Tung University (NYCU), the National Health Research Institutes (NHRI), and Linkou Chang Gung Memorial Hospital have identified a promising solution: **hesperetin**, a natural flavonoid extracted from citrus peel.\
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Their findings, published in the August 2025 issue of *Redox Biology* under the title “[*Activation of CISD2 as a Protective Strategy Against Doxorubicin-Induced Cardiotoxicity,*](https://pubmed.ncbi.nlm.nih.gov/40876442/ "Activation of CISD2 as a Protective Strategy Against Doxorubicin-Induced Cardiotoxicity,")” suggest that hesperetin may counteract Doxorubicin’s cardiotoxic effects without compromising its anti-tumor potency.\
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**Doxorubicin** has been a cornerstone in the treatment of breast cancer, lymphoma, leukemia, and ovarian cancer for over five decades. However, its well-known cardiotoxicity presents a long-standing clinical dilemma. While one FDA-approved cardioprotective drug exists, it also reduces Doxorubicin’s cancer-killing efficacy, increasing the risk of recurrence.\
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The NYCU-led team discovered that Doxorubicin suppresses the expression of the longevity-associated gene **CISD2** in cardiac cells. This suppression disrupts mitochondrial balance and calcium regulation, impairing heart rhythm and contraction. In contrast, **hesperetin reactivates CISD2**, protecting cardiac cells from damage.\
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**From Serendipity to Breakthrough: A Dual Benefit for the Heart and Tumor Control**\
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Remarkably, in animal models, hesperetin not only improved heart function in tumor-bearing mice treated with Doxorubicin but also reduced tumor size—highlighting that it does not blunt Doxorubicin’s anticancer efficacy. The cardioprotective effects of hesperetin were further validated using human induced pluripotent stem cell (iPSC)-derived cardiomyocytes provided by Stanford University, reinforcing its potential for clinical application.\
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The idea for this study was sparked by a casual conversation between Prof. Shu-Ling Fu of NYCU’s Institute of Traditional Medicine and Distinguished Prof. Ting-Fen Tsai of the Department of Life Sciences and Institute of Genome Sciences (DLSIGS).\
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Prof. Fu, who had been searching for natural agents to mitigate chemotherapy-induced side effects, learned that Doxorubicin suppresses CISD2. Prof. Tsai’s team had already identified hesperetin as a CISD2 activator, leading to an interdisciplinary collaboration.\
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Prof. Tsai noted that CISD2 levels decline with age, and her earlier research had confirmed its vital role in maintaining heart function. She emphasized that hesperetin is not the same as hesperidin, a related compound found in citrus peels. Hesperidin has poor bioavailability and must be metabolized by gut probiotics to become hesperetin—the active form that promotes CISD2.

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Simply eating citrus peel, she cautioned, won’t provide sufficient hesperetin. She envisions future applications in which probiotics are used to produce hesperetin as a functional food to counteract chemotherapy-related cardiotoxicity.\
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**Solving a Puzzle with Multidisciplinary Pieces**\
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Co-first authors of the study include Dr. Yi-Ju Chou from NHRI’s Institute of Molecular and Genomic Medicine and Dr. Chi-Hsiao Yeh, cardiovascular surgeon and vice superintendent of Linkou Chang Gung Memorial Hospital.\
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Dr. Yeh explained that Doxorubicin-induced cardiotoxicity is one of the most challenging clinical side effects. Approximately 5–9% of patients develop significant heart failure or cardiomyopathy after treatment. Long-term follow-ups show that 4–10% of patients experience chronic heart failure within a decade of cancer remission.\
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“While these survivors have conquered cancer,” said Dr. Yeh, “they may face progressive cardiac decline years later. If hesperetin can protect the heart without impairing Doxorubicin’s anti-cancer action, it could revolutionize how we approach chemotherapy—making it life-saving without being heartbreaking.”\
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**Research Collaborators**\
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In addition to NYCU, NHRI, and Chang Gung Memorial Hospital, this research involved contributions from:

- Ministry of Health and Welfare’s National Institute of Chinese Medicine
- Chang Gung University
- National Cheng Kung University
- Academia Sinica’s Institute of Biomedical Sciences

*Left: Cardiac cells of a mouse treated with Doxorubicin, showing dark canyon-like damage areas. Right: After hesperetin treatment, the damaged regions begin to recover.*

Related Image(s)：

- [Illustration of Doxorubicin (“Red Berry”) generated by ChatGPT](https://www.nycu.edu.tw/nycu/en/app/news/image?module=headnews&detailNo=1433339253655343104&init=N "Illustration of Doxorubicin (“Red Berry”) generated by ChatGPT(Open New Windows)")

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