Activation of CISD2 as a protective strategy against doxorubicin-induced cardiotoxicity

Yi-Ju Chou; Chi-Hsiao Yeh; Chian-Feng Chen; Chi-Jen Lo; Jian-Hsin Yang; Wen-Tai Chiu; Cheng-Heng Kao; Tsai-Yu Tzeng; Zhao-Qing Shen; Chien-Yi Tung; Chung-Kuang Lu; Mei-Ling Cheng; Patrick C H Hsieh; Shu-Ling Fu; Ting-Fen Tsai

doi:10.1016/j.redox.2025.103840

Activation of CISD2 as a protective strategy against doxorubicin-induced cardiotoxicity

Redox Biol. 2025 Oct:86:103840. doi: 10.1016/j.redox.2025.103840. Epub 2025 Aug 22.

Authors

Yi-Ju Chou¹, Chi-Hsiao Yeh², Chian-Feng Chen³, Chi-Jen Lo⁴, Jian-Hsin Yang⁵, Wen-Tai Chiu⁶, Cheng-Heng Kao⁷, Tsai-Yu Tzeng³, Zhao-Qing Shen⁵, Chien-Yi Tung³, Chung-Kuang Lu⁸, Mei-Ling Cheng⁹, Patrick C H Hsieh¹⁰, Shu-Ling Fu¹¹, Ting-Fen Tsai¹²

Affiliations

¹ Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, 350, Taiwan.
² Department of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital, Linkou, Taoyuan, 333, Taiwan; College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan.
³ Genomics Center for Clinical and Biotechnological Applications, Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.
⁴ Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan, 333, Taiwan.
⁵ Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.
⁶ Department of Biomedical Engineering, College of Engineering, National Cheng Kung University, Tainan, 701, Taiwan.
⁷ Center of General Education, Chang Gung University, Taoyuan, 333, Taiwan.
⁸ Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan; National Research Institute of Chinese Medicine, Taipei, 112, Taiwan.
⁹ Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan, 333, Taiwan; Clinical Metabolomics Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan; Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan.
¹⁰ Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan.
¹¹ Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan. Electronic address: slfu@nycu.edu.tw.
¹² Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, 350, Taiwan; Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan; Center for Healthy Longevity and Aging Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan. Electronic address: tftsai@nycu.edu.tw.

Abstract

Background: Cardiotoxicity of doxorubicin, a chemotherapy medication, remains the most dangerous side effect. CISD2 plays a critical role during cardiac aging.

Objectives: We use a potent CISD2 activator, hesperetin, to ameliorate doxorubicin-induced cardiotoxicity by upregulating CISD2 in mice.

Methods: Two animal models, an acute and a tumor-bearing doxorubicin-induced cardiotoxicity model, were used in this study. Both genetic and pharmacological approaches were employed. Transgenic mice and a potent CISD2 activator, hesperetin, were utilized to ameliorate doxorubicin-induced cardiotoxicity by upregulating CISD2 expression in mice. Additionally, a human-derived iPSC system was used to provide human-relevant evidence. Comprehensive biological, histological, transcriptomic, and metabolomic analyses were conducted.

Results: Five findings are pinpointed. Firstly, doxorubicin suppresses Cisd2 expression resulting in cardiac electromechanical dysfunction. Intriguingly, transgenic overexpression of Cisd2 mitigates doxorubicin-induced cardiotoxicity. Secondly, hesperetin effectively sustains a high level of Cisd2 and improves cardiac function in a Cisd2-dependent manner after doxorubicin treatment. Importantly, hesperetin doesn't influence the anti-cancer efficacy of doxorubicin. Thirdly, doxorubicin downregulates the transcription of CISD2 by decreasing the expression of two transcription regulators, TAF1 and TCF12. Fourthly, analysis of transcriptomic and metabolomic datasets reveals that hesperetin protects the heart via a network connecting glucose, fatty acids and amino acids metabolism, thereby ensuring a sufficient energy supply. Additionally, hesperetin improves antioxidation capacity via reinstating the pentose phosphate and glutathione pathways. Finally, in human iPSC-derived cardiomyocytes, hesperetin significantly upregulates CISD2 and protects the cells from doxorubicin-induced toxicity and functional damage.

Conclusions: Our results highlight the potential utility of Cisd2 and its activator hesperetin in chemotherapy involving doxorubicin.

Keywords: CISD2; Cardiotoxicity; Doxorubicin; Hesperetin; iPSC derived cardiomyocytes.

MeSH terms

Animals
Cardiotoxicity* / etiology
Cardiotoxicity* / genetics
Cardiotoxicity* / metabolism
Cardiotoxicity* / pathology
Cardiotoxicity* / prevention & control
Disease Models, Animal
Doxorubicin* / adverse effects
Hesperidin* / pharmacology
Humans
Mice
Mice, Transgenic
Myocytes, Cardiac / drug effects
Myocytes, Cardiac / metabolism

Substances

Doxorubicin
Hesperidin
hesperetin