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Peer-reviewedCC BYAdvanced science (Weinheim, Baden-Wurttemberg, Germany)

ALDH2 Suppresses Ferroptosis and Promotes Bortezomib Resistance in Multiple Myeloma Through the KEAP1-NRF2 Feedback Loop.

  • Ruonan Shao1
  • Chengcheng Liu2
  • Xinpei Deng1
  • Jindong Xie1
  • Wenjian Liu1
  • Bin Yang3
  • Lingrui Liu1
  • Cailu Song1
  • Lei Li1,4
  • Hua Wang1
  • Hailin Tang1
4 affiliations
  1. 1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.
  2. 2Department of Hematology, The Third Affiliated Hospital of Sun Yat Sen University, Guangzhou, People's Republic of China.
  3. 3Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  4. 4Department of Pathology, the First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, People's Republic of China.
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Abstract

Resistance to bortezomib (BTZ) represents a major obstacle that limits the therapeutic efficacy and worsens the prognosis of multiple myeloma (MM). Ferroptosis, a form of regulated cell death triggered by excessive lipid peroxidation, has garnered increasing attention for anticancer intervention, yet the mechanisms underlying ferroptosis in MM remain enigmatic. Here, we confirmed that ALDH2 is upregulated in MM patients and that its altered expression is closely associated with BTZ resistance and poor prognosis. Functionally, ALDH2 promoted the proliferation, BTZ resistance, and ferroptosis resistance of MM cells, suggesting its oncogenic role. Mechanistically, ALDH2 competitively bound to KEAP1 and stabilized NRF2 by preventing its ubiquitin-proteasome-mediated degradation, thereby promoting the nuclear translocation of NRF2 and subsequent upregulation of GPX4, and in turn regulating ferroptosis, proliferation, and BTZ resistance in MM. In parallel, NRF2 bound directly to the promoter region of ALDH2 and further enhanced ALDH2 transcription, thus forming a positive feedback loop. Collectively, our findings reveal that the ALDH2/KEAP1/NRF2-GPX4 axis may serve as a key regulator of ferroptosis in MM and a promising therapeutic target for overcoming BTZ resistance.

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Cite

BibTeXRIS
BibTeX
@article{shao2026aldh2,
  title = {{ALDH2 Suppresses Ferroptosis and Promotes Bortezomib Resistance in Multiple Myeloma Through the KEAP1-NRF2 Feedback Loop.}},
  author = {Ruonan Shao and Chengcheng Liu and Xinpei Deng and Jindong Xie and Wenjian Liu and Bin Yang and Lingrui Liu and Cailu Song and Lei Li and Hua Wang and Hailin Tang},
  journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
  year = {2026},
  month = oct,
  doi = {10.1002/advs.78403},
  url = {https://europepmc.org/article/MED/42949631},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - ALDH2 Suppresses Ferroptosis and Promotes Bortezomib Resistance in Multiple Myeloma Through the KEAP1-NRF2 Feedback Loop.
AU  - Ruonan Shao
AU  - Chengcheng Liu
AU  - Xinpei Deng
AU  - Jindong Xie
AU  - Wenjian Liu
AU  - Bin Yang
AU  - Lingrui Liu
AU  - Cailu Song
AU  - Lei Li
AU  - Hua Wang
AU  - Hailin Tang
PY  - 2026
DA  - 2026/10/28
JO  - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
DO  - 10.1002/advs.78403
UR  - https://europepmc.org/article/MED/42949631
AB  - Resistance to bortezomib (BTZ) represents a major obstacle that limits the therapeutic efficacy and worsens the prognosis of multiple myeloma (MM). Ferroptosis, a form of regulated cell death triggered by excessive lipid peroxidation, has garnered increasing attention for anticancer intervention, yet the mechanisms underlying ferroptosis in MM remain enigmatic. Here, we confirmed that ALDH2 is upregulated in MM patients and that its altered expression is closely associated with BTZ resistance and poor prognosis. Functionally, ALDH2 promoted the proliferation, BTZ resistance, and ferroptosis resistance of MM cells, suggesting its oncogenic role. Mechanistically, ALDH2 competitively bound to KEAP1 and stabilized NRF2 by preventing its ubiquitin-proteasome-mediated degradation, thereby promoting the nuclear translocation of NRF2 and subsequent upregulation of GPX4, and in turn regulating ferroptosis, proliferation, and BTZ resistance in MM. In parallel, NRF2 bound directly to the promoter region of ALDH2 and further enhanced ALDH2 transcription, thus forming a positive feedback loop. Collectively, our findings reveal that the ALDH2/KEAP1/NRF2-GPX4 axis may serve as a key regulator of ferroptosis in MM and a promising therapeutic target for overcoming BTZ resistance.
SN  - 2198-3844
ER  -