The role of RAD23A in DNA repair and proteasome-dependent protein degradation in multiple myeloma

Multiple myeloma (MM) is a plasma cell malignancy characterized by genomic instability and a high dependency on proteasome activity. Accordingly, DNA-damaging agents and proteasome inhibitors (PIs) are frontline therapies; however, therapeutic resistance inevitably develops. RAD23A, a dual-function protein involved in nucleotide excision repair and proteasome-mediated protein degradation, is highly expressed in MM and is associated with poor patient survival. Here, we demonstrate that depletion of RAD23A exerts potent anti-MM activity both in vitro and in vivo. Inducible CRISPR/Cas9 knockout (iKO) or shRNA-mediated knockdown of RAD23A in MM cell lines, including PI-resistant models, markedly suppressed cell proliferation. RAD23A loss impaired DNA repair capacity, triggered activation of the stress-associated eIF2α-ATF4 axis and promoted caspase-dependent apoptosis. Quantitative proteomic profiling of RAD23A-iKO cells confirmed upregulation of apoptotic and stress-response pathways, accompanied by downregulation of DNA repair and deubiquitination pathways. In an MM xenograft model, RAD23A depletion significantly reduced tumor growth and prolonged survival. Collectively, these findings identify RAD23A as a critical survival factor in MM and highlight its potential as a novel therapeutic target.