尽管全球广泛关注癌症治疗后大量患者发生心血管疾病的问题，但明确的预防和治疗策略仍然难以捉摸。在这项研究中，我们使用人类诱导多能干细胞来源的心肌细胞（hiPSC-CM）建立了系统来评估抗癌药物对线粒体质量控制的影响，线粒体对于能量代谢至关重要。奥西替尼是一种表皮生长因子受体酪氨酸激酶抑制剂，用于治疗肺癌，据报道会增加心血管疾病的风险。然而，其根本机制在很大程度上尚不清楚。在这里，我们发现用奥希替尼和多柔比星（而不是曲妥珠单抗和顺铂）治疗 hiPSC-CM，显示出伴随线粒体裂变的浓度依赖性呼吸功能损害。我们之前报道过硫代谢在维持心脏线粒体质量方面的重要作用。各种无机硫供体（Na2S、Na2S2、Na2S3）与抗癌药物的共同治疗表明，Na2S 减轻了奥希替尼的心脏毒性，但不能减轻阿霉素。奥希替尼降低了细胞内还原硫水平，而Na2S处理抑制了硫泄漏，表明其在减轻奥希替尼引起的心脏毒性方面具有潜力。这些结果意味着无机硫化物（例如 Na2S）作为精准药物治疗的种子来减轻奥希替尼的心脏毒性作用的前景。版权所有 © 2024 作者。由 Elsevier B.V. 制作和托管。保留所有权利。

Despite the widespread recognition of the global concern regarding the onset of cardiovascular diseases in a significant number of patients following cancer treatment, definitive strategies for prevention and treatment remain elusive. In this study, we established systems to evaluate the influence of anti-cancer drugs on the quality control of mitochondria, pivotal for energy metabolism, using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor used for treatment in lung cancer, reportedly increases the risk of cardiovascular disease. However, its underlying mechanism is largely unknown. Here, we found that the treatment of hiPSC-CMs with osimertinib and doxorubicin, but not trastuzumab and cisplatin, revealed a concentration-dependent impairment of respiratory function accompanied by mitochondrial fission. We previously reported the significant role of sulfur metabolism in maintaining mitochondrial quality in the heart. Co-treatment with various inorganic sulfur donors (Na2S, Na2S2, Na2S3) alongside anti-cancer drugs demonstrated that Na2S attenuated the cardiotoxicity of osimertinib but not doxorubicin. Osimertinib decreased intracellular reduced sulfur levels, while Na2S treatment suppressed the sulfur leakage, suggesting its potential in mitigating osimertinib-induced cardiotoxicity. These results imply the prospect of inorganic sulfides, such as Na2S, as a seed for precision pharmacotherapy to alleviate osimertinib's cardiotoxic effects.Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.