Anthracyclines attenuate Nrf1-dependent proteolytic pathways and potentiate proteasome inhibitor cytotoxicity.

ABSTRACT: Proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib are FDA-approved treatments for multiple myeloma, but resistance frequently limits their effectiveness. The transcription factor Nrf1 (NFE2L1) upregulates proteasome and autophagy genes upon proteasome inhibition, contributing to adaptive resistance. In this study, we identified anthracyclines, including doxorubicin, as suppressors of the Nrf1-driven transcriptional response. Mechanistically, doxorubicin impaired Nrf1 binding to antioxidant response elements (AREs) within promoter regions of target genes without affecting Nrf1 processing or nuclear localization. Importantly, aclarubicin, a non-DNA-damaging anthracycline, also attenuated Nrf1 transcriptional activity, indicating that DNA damage is not required for this inhi

SUBMITTER: Vangala JR 

PROVIDER: S-EPMC12574707 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature