Carfilzomib Induces Cardiotoxicity by Blocking Autophagic Flux Through the cGAS-STING Signaling Pathway

Carfilzomib (CFZ) is a proteasome inhibitor primarily used to treat relapsed and refractory multiple myeloma. However, its clinical application is limited by significant cardiotoxicity, the underlying mechanisms of which remain incompletely understood. In this study, we aimed to elucidate the pathogenic pathways involved. In vitro, CFZ induced mitochondrial dysfunction and apoptosis in AC16 cardiomyocytes in a concentration- and time-dependent manner. Transcriptomic analysis revealed enrichment in pathways related to autophagy and endoplasmic reticulum stress. Mechanistically, CFZ promoted autophagosome formation but downregulated the SNARE proteins STX17, SNAP29, and VAMP8, thereby impairing autophagosome–lysosome fusion and blocking autophagic flux. This disruption was associated with the activation of the cGAS-STING signaling pathway. In vivo, CFZ administration resulted in cardiac dysfunction and apoptosis in mice, both of which were attenuated by the STING inhibitor C-176. Consistently, STING knockdown restored autophagic flux and reduced cardiomyocyte injury in vitro. In conclusion, CFZ induces cardiotoxicity by activating the cGAS-STING pathway, which disrupts the autophagic clearance of damaged mitochondria and promotes cardiomyocyte apoptosis. Targeting STING may represent a promising therapeutic strategy to mitigate CFZ-induced cardiotoxicity.