Atorvastatin Protects Against Carfilzomib-Induced Deleterious Transcriptional Changes in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

The mechanisms underlying carfilzomib (CFZ)-induced cardiotoxicity remain incompletely elucidated. In this study, we used human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) to char-acterize the transcriptional impact of CFZ and to evaluate whether atorvastatin could prevent these dele-terious transcriptional changes. hiPSC-CMs were treated with 1 µM CFZ, CFZ + atorvastatin, atorvastatin, or vehicle control, followed by RNA sequencing and differential expression analysis and pathway analyses. Transcriptomic profiling revealed a marked upregulation of genes in multiple proteasome subunits, in-cluding ATPase components (PSMC1, PSMC4, PSMC5, PSMC6) and non-ATPase regulatory subunits (PSMD1, PSMD2, PSMD12), suggesting a strong compensatory activation of proteostasis and protein quality-control pathways in response to CFZ exposure. In addition, several of the most significantly altered genes were those implicated in cardiovascular disease and heart failure, such as BAG3 and FLNC and many heat-shock proteins, indicating activation of cardiac stress-response pathways relevant to CFZ-associated cardiotoxicity. Atorvastatin co-treatment partially reversed a subset of CFZ-induced transcriptional changes, particularly within cholesterol biosynthesis and lipid regulatory pathways (e.g. ACAT2 and ACTA1), but did not restore CFZ-mediated downregulation of sarcomeric genes. Together, these findings define a mul-tifactorial signature of CFZ-induced deleterious transcriptional changes and suggest that atorvastatin may provide partial metabolic, but not structural, cardioprotection.