Mendez-Lopez Max, Besse Andrej, Zuppinger Christian, Perez-Shibayama Christian, Gil-Cruz Cristina, Florea Bogdan I, De Martin Angelina, Lütge Mechthild, Beckerova Deborah, Klimovic Simon, Zhou Xiang, Rasche Leo, Pribyl Jan, Rotrekl Vladimir, Ludewig Burkhard, Overkleeft Herman S, Besse Lenka, Driessen Christoph
Laboratory of Experimental Oncology, Division Oncology and Hematology, HOCH Health Ostschweiz, Cantonal Hospital St. Gallen, 9007 St. Gallen, Switzerland.
Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic.
iScience. 2025 Jul 29;28(9):113228. doi: 10.1016/j.isci.2025.113228. eCollection 2025 Sep 19.
Compared to bortezomib treatment, multiple myeloma (MM) treatment with the proteasome inhibitor carfilzomib is associated with a higher incidence of cardiovascular adverse events. However, the mechanism underlying such cardiopathogenic side effects in MM patients remains elusive. Here, we show that carfilzomib-specific proteasome inhibition profoundly impairs cardiomyocyte contractility. Using an unbiased multiomics approach and , followed by validation, we elucidated carfilzomib-related changes in contractility proteins and cellular translation, retinol oxidative metabolism, and the angiotensin II derivative, angiotensin A. Subsequently, all-trans retinoic acid and angiotensin II type 1 receptor inhibitor prevented cardiomyocytes from experiencing carfilzomib-induced toxicity in human and murine and models through stabilization of protein and metabolic homeostasis. Our data reveal a mechanism underlying carfilzomib-induced cardiotoxicity that closely mirrors clinical observations and may open new avenues for management of such potentially lethal side effects in patients with MM.
与硼替佐米治疗相比，蛋白酶体抑制剂卡非佐米治疗多发性骨髓瘤（MM）与心血管不良事件的更高发生率相关。然而，MM患者中这种致心脏病变副作用的潜在机制仍不清楚。在此，我们表明卡非佐米特异性蛋白酶体抑制会严重损害心肌细胞收缩力。通过一种无偏倚的多组学方法并随后进行验证，我们阐明了与卡非佐米相关的收缩力蛋白和细胞翻译、视黄醇氧化代谢以及血管紧张素II衍生物血管紧张素A的变化。随后，全反式维甲酸和血管紧张素II 1型受体抑制剂通过稳定蛋白质和代谢稳态，在人和小鼠模型中防止心肌细胞遭受卡非佐米诱导的毒性。我们的数据揭示了卡非佐米诱导心脏毒性的一种机制，该机制与临床观察结果密切相符，并可能为管理MM患者中这种潜在致命副作用开辟新途径。
