• Carfilzomib induces cardiotoxicity by suppressing SENP1 expression in cardiomyocytes, leading to myocardial hypertrophy and injury.
• SENP1 directly deSUMOylates DDX17, promoting its degradation via K-48 ubiquitination and thereby maintaining mitochondrial homeostasis and anti-apoptotic gene expression.
• Overexpression of SENP1 via AAV vectors alleviates Cfz-induced cardiotoxicity in mice, highlighting a potential therapeutic strategy.
• The SENP1-DDX17 axis represents a novel protective mechanism against proteasome inhibitor cardiotoxicity, offering a foundation for clinical interventions in multiple myeloma patients.