The role of KPNA3 in multiple myeloma: implications for targeting nuclear import.

Multiple myeloma (MM) is an incurable tumor of malignant plasma cells. Importin α4, also known as KPNA3, is a component of the importin α/β system, which contributes to the cytosol-to-nucleus trafficking of cellular substances. In this study, we discovered that KPNA3 was highly expressed in MM and that its expression level inversely correlated with patient prognosis. Both in vitro and in vivo experiments demonstrated that the knockdown of KPNA3 inhibited the proliferation of MM cells, promoted their apoptosis and increased their drug sensitivity. Mechanistic investigations also revealed that the knockdown of KPNA3 inhibited ALDH2 transcription and downregulated the activity of the hedgehog pathway. Additionally, we demonstrated the direct binding of ivermectin (IVM) to KPNA3, a functional component of the importin α/β system. IVM can significantly reduce KPNA3 protein levels and promote apoptosis in MM cells. Finally, both in vitro and in vivo experiments revealed that IVM and selinexor exhibited synergistic anti-MM activities. Overall, our study reveals the role of KPNA3 in MM and suggests that targeting its nuclear import is a promising MM treatment.