2. Academic Validation
  3. Carfilzomib-specific proteasome β5/β2 inhibition drives cardiotoxicity via remodeling of protein homeostasis and the renin-angiotensin-system

Carfilzomib-specific proteasome β5/β2 inhibition drives cardiotoxicity via remodeling of protein homeostasis and the renin-angiotensin-system

  • iScience. 2025 Jul 29;28(9):113228. doi: 10.1016/j.isci.2025.113228.
Max Mendez-Lopez 1,  Andrej Besse 1 2,  Christian Zuppinger 3,  Christian Perez-Shibayama 4,  Cristina Gil-Cruz 4,  Bogdan I Florea 5,  Angelina De Martin 4,  Mechthild Lütge 4,  Deborah Beckerova 2 6,  Simon Klimovic 7,  Xiang Zhou 8,  Leo Rasche 8 9,  Jan Pribyl 10,  Vladimir Rotrekl 2 6,  Burkhard Ludewig 4,  Herman S Overkleeft 5,  Lenka Besse 1 2,  Christoph Driessen 1
Affiliations

Affiliations

  • 1 Laboratory of Experimental Oncology, Division Oncology and Hematology, HOCH Health Ostschweiz, Cantonal Hospital St. Gallen, 9007 St. Gallen, Switzerland.
  • 2 Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic.
  • 3 Department for Biomedical Research, Department of Cardiology, Bern University Hospital, 3008 Bern, Switzerland.
  • 4 Institute of Immunobiology, HOCH Health Ostschweiz, Cantonal Hospital St. Gallen, 9007 St. Gallen, Switzerland.
  • 5 Gorlaeus Building, Leiden Institute of Chemistry, 2333 Leiden, the Netherlands.
  • 6 ICRC, St Anne's University Hospital, 65691 Brno, Czech Republic.
  • 7 Department of Biochemistry, Faculty of Science, Masaryk University, 62500 Brno, Czech Republic.
  • 8 Department of Internal Medicine II, University Hospital of Würzburg, 97080 Würzburg, Germany.
  • 9 Mildred Scheel Early Career Center, University Hospital of Würzburg, 97080 Würzburg, Germany.
  • 10 CEITEC, Masaryk University, 62500 Brno, Czech Republic.
PMID: 40894880 DOI: 10.1016/j.isci.2025.113228
Abstract

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 in vitro and in vivo, followed by in vitro 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 in vitro and in vivo 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.

Keywords

Biological sciences; Natural sciences; Pharmacology; Physiology.

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