Aims Doxorubicin (DOX) is a widely used anthracycline anticancer agent; however, its irreversible effects on the heart can result in DOX-induced cardiotoxicity (DICT) after cancer treatment. Unfortunately, the pathophysiology of DICT has not yet been fully elucidated, and there are no effective strategies for its prevention or treatment. In this investigation, the novel role of transducin beta-like protein 1 (TBL1) in developing and regulating DICT was explored. Methods and results We observed a reduction in TBL1 protein expression levels as well as cleavage events in the transplanted cardiac tissues of patients diagnosed with Dilated Cardiomyopathy (DCM) and DICT. It was revealed that DOX selectively induces TBL1 cleavage at caspase-3 preferred sites—D125, D136, and D215. Interestingly, overexpression of the uncleaved TBL1 mutant (TBL1uclv) variant reduced apoptosis, effectively preventing DOX-induced cell death. We confirmed that cleaved TBL1 cannot form a complex with β-catenin. As a result, Wnt reporter activity, and Wnt target gene expression collectively indicate a decrease in Wnt/β-catenin signaling, leading to DICT progression. Furthermore, the cleaved TBL1 triggered DOX-induced abnormal electrophysiological features and disrupted calcium homeostasis. However, these effects were improved in TBL1uclv-overexpressing human-induced pluripotent stem cell-derived cardiomyocytes. Finally, in a DICT mouse model, TBL1uclv overexpression inhibited the DICT-induced reduction of cardiac contractility and collagen accumulation, ultimately protecting cardiomyocytes from cell death. Conclusions Our findings reveal that the inhibition of TBL1 cleavage not only mitigates apoptosis but also enhances cardiomyocyte function, even in the context of DOX administration. Consequently, this study's results suggest that inhibiting TBL1 cleavage may be a novel strategy to ameliorate DICT.

中文翻译：

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抑制 TBL1 裂解通过调节 Wnt/β-catenin 信号通路减轻阿霉素诱导的心肌细胞死亡

目的 多柔比星 (DOX) 是一种广泛使用的蒽环类抗癌药物；然而，它对心脏的不可逆影响可能会在癌症治疗后导致 DOX 诱导的心脏毒性 (DICT)。不幸的是，DICT的病理生理学尚未完全阐明，也没有有效的预防或治疗策略。在这项研究中，探讨了转导蛋白 β 样蛋白 1 (TBL1) 在发展和调节 DICT 中的新作用。方法和结果 我们观察到诊断为扩张型心肌病 (DCM) 和 DICT 的患者移植心脏组织中 TBL1 蛋白表达水平以及裂解事件降低。结果表明，DOX 选择性诱导 TBL1 在 caspase-3 首选位点（D125、D136 和 D215）处裂解。有趣的是，未切割的 TBL1 突变体 (TBL1uclv) 的过度表达可减少细胞凋亡，有效防止 DOX 诱导的细胞死亡。我们证实切割的 TBL1 不能与 β-连环蛋白形成复合物。因此，Wnt 报告基因活性和 Wnt 靶基因表达共同表明 Wnt/β-catenin 信号传导减少，导致 DICT 进展。此外，裂解的 TBL1 引发 DOX 诱导的异常电生理特征并破坏钙稳态。然而，这些效应在 TBL1uclv 过表达的人诱导多能干细胞来源的心肌细胞中得到改善。最后，在 DICT 小鼠模型中，TBL1uclv 过表达抑制了 DICT 诱导的心肌收缩力和胶原蛋白积累的减少，最终保护心肌细胞免于细胞死亡。结论 我们的研究结果表明，即使在给予 DOX 的情况下，抑制 TBL1 裂解不仅可以减轻细胞凋亡，还可以增强心肌细胞功能。因此，本研究的结果表明，抑制 TBL1 裂解可能是改善 DICT 的新策略。