RAD23A promotes multiple myeloma cell survival through DNA damage response, proteostasis and enhanced metabolic activity.

Multiple myeloma (MM) remains incurable and is characterized by the abnormal proliferation of malignant plasma cells in the bone marrow. RAD23A is a multifunctional protein involved in the ubiquitin-proteasome system (UPS) and DNA damage repair; however, its role in MM remains unclear. Here, we analyzed RAD23A expression and its prognostic relevance across multiple MM cohorts. The biological functions of RAD23A in MM cells were predicted using bulk RNA-seq and single-cell RNA-seq data. Experimental validation was performed in H929 and RPMI8226 MM cell lines. Flow cytometry was used to assess cell cycle progression and apoptosis. Oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and glucose uptake assays were performed to evaluate mitochondrial respiration, glycolytic activity, and glucose uptake, respectively, and RNA sequencing was conducted to further verify the role of RAD23A in MM. Our results showed that RAD23A is upregulated in MM and that high RAD23A expression is associated with greater disease burden and more advanced disease stage. Bioinformatics analyses revealed that RAD23A high MM cells exhibited elevated metabolic activity and increased protein transport. RAD23A knockdown suppressed MM cell growth both in vitro and in vivo, induced DNA damage and endoplasmic reticulum stress, and caused G2/M cell cycle arrest and apoptosis. Moreover, RAD23A knockdown enhanced the sensitivity of MM cells to bortezomib (BTZ) and impaired mitochondrial respiration, glycolytic activity, and glucose uptake. These findings suggest that RAD23A may serve as a multifunctional regulator and potential therapeutic target in MM.