隨著對心臟腫瘤學愈來愈被重視，如何早期診斷和治療癌症治療相關心臟功能障礙變得相當重要。Empagliflozin是種鈉-葡萄糖協同轉運蛋白2抑制劑，且在臨床上對心衰竭有顯著的功效，但鈉-葡萄糖協同轉運蛋白2主要並非表現在心臟細胞，所以empagliflozin對心臟的機轉以及是否對癌症治療心毒性有效仍未知。
我們首先使用斑點追蹤心臟超音波來成功偵測癌症治療所導致之心毒性，發現即使在安全劑量的doxorubicin使用下依然有近一半的病人有心臟功能下降，並證實這群病人有較差之運動肺功能以及臨床預後。接著，我們使用iPSC-CM作為平台證實empagliflozin可以直接作用於心臟細胞，且可以減少doxorubicin對心臟細胞所造成的細胞凋亡。而在相關路徑的實驗中發現doxorubicin造成JNK/STAT3軸的磷酸化，且empagliflozin可以經由抑制JNK減少doxorubicin所造成之細胞凋亡，顯示JNK在此心毒性上的重要角色。接著我們發現活性氧物質以及NAD+是造成此心毒性的JNK下游路徑。最後，我們使用動物研究再次證實empagliflozin可減輕doxorubicin誘導的心臟功能障礙，且由於抑制JNK有同樣的效果，表示empagliflozin對心臟的幫助並非只是經由利尿而是經由JNK的抑制。另外，由於臨床僅使用安全劑量而非高劑量之doxorubicin，因此我們探討安全劑量藥物下的加成心毒性，發現vincristine會加強doxorubicin之心毒性，且機轉可能是經由加強JNK之磷酸化，而empagliflozin對此加成心毒性依然有保護效果，再次展現了empagliflozin在doxorubicin導致之心毒性的重要保護腳色，我們的研究結果值得擴展到後續的臨床隨機試驗以驗證empagliflozin在臨床使用的角色。

As the field of cardiac oncology gains importance, early diagnosis and management of cancer treatment-related cardiac dysfunction (CTRCD) have become crucial. Empagliflozin, a sodium-glucose cotransporter 2 inhibitor, has shown significant efficacy in heart failure management. However, its mechanisms of action in cardiomyocyte and potential effectiveness against doxorubicin-induced CTRCD remain unclear.
Our study employed speckle tracking echocardiography to detect cardiotoxicity from cancer treatment, revealing that nearly half of the patients experienced cardiac function decline even at safe doses of doxorubicin. These patients also exhibited poorer exercise capacity and clinical outcomes. Then, using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM), we confirmed that empagliflozin directly impacts cardiomyocyte and reduces doxorubicin-induced apoptosis. Mechanistically, doxorubicin was found to activate the JNK/STAT3 pathway, while empagliflozin inhibited JNK, thus mitigating cell apoptosis and highlighting JNK’s critical role in this cardiotoxicity. Our findings identified reactive oxygen species and NAD+ as downstream pathways associated with JNK in this context. In animal studies, empagliflozin was further shown to alleviate doxorubicin-induced cardiac dysfunction, with JNK inhibition suggesting that its protective effects extend beyond diuresis. Furthermore, we explored the additive cardiotoxicity of low-dose doxorubicin combined with vincristine, which appeared to exacerbate cardiac toxicity via enhanced JNK phosphorylation. Notably, empagliflozin maintained its protective effects against this combined cardiotoxicity without compromising the efficacy of lymphoma treatment. Our findings warrant further clinical trials to validate the application of empagliflozin in managing CTRCD, given the critical need for strategies that protect cardiac function in cancer survivors.

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