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IRX4204 sensitizes multiple myeloma to ferroptosis and improves lenalidomide efficacy through the HMOX1-GPX4 axis
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  • Published: 17 March 2026

IRX4204 sensitizes multiple myeloma to ferroptosis and improves lenalidomide efficacy through the HMOX1-GPX4 axis

  • Jian Wu1,
  • Zhibo Yan2,
  • Kimberly Burcher1,
  • Zhannan Han2,
  • Mikhail A. Nikiforov2,3,
  • Vidyasagar Vuligonda4,
  • Martin Sanders4 &
  • …
  • Yubin Kang1 

Scientific Reports , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Cancer
  • Cell biology
  • Diseases
  • Drug discovery

Abstract

Despite advances in therapy, multiple myeloma (MM) largely remains incurable, emphasizing the need for new strategies to overcome drug resistance. Ferroptosis is an iron-dependent cell death pathway that may present a therapeutic vulnerability in MM, but its transcriptional regulation remains poorly understood. Retinoid X receptors (RXRs) are ligand-activated nuclear transcription factors that regulate metabolism, redox homeostasis, and immune signaling. In this study, we demonstrate that RXR signaling regulates ferroptosis. The selective third-generation RXR agonist IRX4204 significantly increased MM cells’ susceptibility to ferroptotic stress and worked synergistically with ferroptosis inducers. Mechanistic studies showed that IRX4204 actively induces HMOX1 transcription via PPARα-RXRα binding and concurrently decreases GPX4 levels, leading to iron buildup, lipid peroxidation, and ferroptosis. Deleting HMOX1 using CRISPR abolished these effects, confirming HMOX1 as an essential effector. In vivo, IRX4204 enhanced lenalidomide’s effectiveness, reduced tumor burden, extended survival, and elevated ferroptosis markers without added toxicity. Clinically, high HMOX1 expression correlates with improved overall survival in MM patients. These findings reveal a new RXR–HMOX1–GPX4 regulatory axis, establish RXR activation as a method to boost ferroptosis sensitivity, and support combining RXR agonists with ferroptosis-based treatments in MM.

Data availability

The data presented in this study are available on request from the corresponding author.

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Funding

This research was funded by National Cancer Institute grant numbers R21CA234701, R21CA280499, and R21CA267275 (YK); National Heart, Lung and Blood Institute grant numbers R56HL155582 (YK); National Institute of Allergy And Infectious Diseases under Award Number U19AI067798.

Author information

Authors and Affiliations

  1. Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC, 27710, USA

    Jian Wu, Kimberly Burcher & Yubin Kang

  2. Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA

    Zhibo Yan, Zhannan Han & Mikhail A. Nikiforov

  3. Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA

    Mikhail A. Nikiforov

  4. Io Therapeutics, Inc, Spring, TX, 77387, USA

    Vidyasagar Vuligonda & Martin Sanders

Authors
  1. Jian Wu
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  2. Zhibo Yan
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  3. Kimberly Burcher
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  5. Mikhail A. Nikiforov
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Contributions

JW and YK conceived and designed the study. JW performed the experiments. JW, ZY, ZH, KB, and MN analyzed and interpreted the data. JW and YK wrote the original draft. All authors contributed to critical revision and editing of the manuscript. YK supervised the study.

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Correspondence to Yubin Kang.

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Wu, J., Yan, Z., Burcher, K. et al. IRX4204 sensitizes multiple myeloma to ferroptosis and improves lenalidomide efficacy through the HMOX1-GPX4 axis. Sci Rep (2026). https://doi.org/10.1038/s41598-026-42123-9

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  • Received: 25 November 2025

  • Accepted: 24 February 2026

  • Published: 17 March 2026

  • DOI: https://doi.org/10.1038/s41598-026-42123-9

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