Chou Yi-Ju, Yeh Chi-Hsiao, Chen Chian-Feng, Lo Chi-Jen, Yang Jian-Hsin, Chiu Wen-Tai, Kao Cheng-Heng, Tzeng Tsai-Yu, Shen Zhao-Qing, Tung Chien-Yi, Lu Chung-Kuang, Cheng Mei-Ling, Hsieh Patrick C H, Fu Shu-Ling, Tsai Ting-Fen
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, 350, Taiwan.
Department of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital, Linkou, Taoyuan, 333, Taiwan; College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan.
Redox Biol. 2025 Aug 22;86:103840. doi: 10.1016/j.redox.2025.103840.
Cardiotoxicity of doxorubicin, a chemotherapy medication, remains the most dangerous side effect. CISD2 plays a critical role during cardiac aging.
We use a potent CISD2 activator, hesperetin, to ameliorate doxorubicin-induced cardiotoxicity by upregulating CISD2 in mice.
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.
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.
Our results highlight the potential utility of Cisd2 and its activator hesperetin in chemotherapy involving doxorubicin.
化疗药物阿霉素的心脏毒性仍然是最危险的副作用。CISD2在心脏衰老过程中起关键作用。
我们使用一种强效的CISD2激活剂橙皮素，通过上调小鼠体内的CISD2来改善阿霉素诱导的心脏毒性。
本研究使用了两种动物模型，即急性和荷瘤阿霉素诱导的心脏毒性模型。采用了基因和药理学方法。利用转基因小鼠和一种强效的CISD2激活剂橙皮素，通过上调小鼠体内CISD2的表达来改善阿霉素诱导的心脏毒性。此外，还使用了人源诱导多能干细胞系统来提供与人类相关的证据。进行了全面的生物学、组织学、转录组学和代谢组学分析。
确定了五项发现。首先，阿霉素抑制Cisd2表达，导致心脏机电功能障碍。有趣的是，Cisd2的转基因过表达减轻了阿霉素诱导的心脏毒性。其次，橙皮素在阿霉素治疗后以Cisd2依赖的方式有效维持Cisd2的高水平并改善心脏功能。重要的是，橙皮素不影响阿霉素的抗癌疗效。第三，阿霉素通过降低两种转录调节因子TAF1和TCF12的表达来下调CISD2的转录。第四，转录组学和代谢组学数据集分析表明，橙皮素通过连接葡萄糖、脂肪酸和氨基酸代谢的网络保护心脏，从而确保充足的能量供应。此外，橙皮素通过恢复磷酸戊糖途径和谷胱甘肽途径提高抗氧化能力。最后，在人诱导多能干细胞衍生的心肌细胞中，橙皮素显著上调CISD2，并保护细胞免受阿霉素诱导的毒性和功能损伤。
我们的结果突出了Cisd2及其激活剂橙皮素在涉及阿霉素的化疗中的潜在用途。
