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

Hongmei Luo1, Ziyue Mi2, Jingcao Huang2

  • 1Department of Hematology/Institute of Hematology Research, West China Hospital, Sichuan University, Chengdu, China. 957646155@qq.com.

Apoptosis : an International Journal on Programmed Cell Death
|March 12, 2026
PubMed

Insights

Importin α4 (KPNA3) is highly expressed in multiple myeloma (MM) and drives tumor growth. Targeting KPNA3 with ivermectin (IVM) shows promise for MM treatment by inhibiting proliferation and promoting apoptosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Multiple myeloma (MM) is a malignant plasma cell tumor with no current cure.
  • Importin α4 (KPNA3) is part of the importin α/β system, crucial for transporting substances into the cell nucleus.
  • The role of KPNA3 in MM pathogenesis and its therapeutic potential are largely unexplored.

Purpose of the Study:

  • To investigate the expression and function of KPNA3 in multiple myeloma.
  • To explore the therapeutic potential of targeting KPNA3 in MM.
  • To identify novel therapeutic strategies for MM.

Main Methods:

  • Quantitative analysis of KPNA3 expression in MM patient samples.
  • In vitro and in vivo studies involving KPNA3 knockdown in MM cells.
  • Investigation of KPNA3's effect on ALDH2 transcription and hedgehog pathway activity.
  • Assessment of ivermectin (IVM) binding to KPNA3 and its effects on MM cells.
  • Evaluation of synergistic effects of IVM and selinexor in MM models.

Main Results:

  • KPNA3 is highly expressed in MM, with higher levels correlating with poorer patient prognosis.
  • KPNA3 knockdown inhibited MM cell proliferation, induced apoptosis, and enhanced drug sensitivity.
  • KPNA3 knockdown suppressed ALDH2 transcription and downregulated hedgehog pathway activity.
  • Ivermectin (IVM) directly binds to KPNA3, reducing its protein levels and promoting MM cell apoptosis.
  • IVM and selinexor demonstrated synergistic anti-MM activity in vitro and in vivo.

Conclusions:

  • KPNA3 plays a significant role in the development and progression of multiple myeloma.
  • Targeting the nuclear import mediated by KPNA3 presents a promising therapeutic strategy for MM.
  • Ivermectin (IVM) emerges as a potential therapeutic agent for MM, particularly in combination therapy.
Keywords:
HedgehogIvermectinKPNA3Multiple myelomaProliferation

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