2. Academic Validation
  3. HDAC inhibitor enhances ferroptosis susceptibility of AML cells by stimulating iron metabolism

HDAC inhibitor enhances ferroptosis susceptibility of AML cells by stimulating iron metabolism

  • Cell Signal. 2025 Mar:127:111583. doi: 10.1016/j.cellsig.2024.111583.
Ruipeng Bian 1,  Yingying Shang 2,  Nahua Xu 3,  Baiping Liu 3,  Yanni Ma 2,  Hui Li 4,  Jieping Chen 5,  Qi Yao 6
Affiliations

Affiliations

  • 1 Guizhou University Medical College, Guiyang 550025, Guizhou Province, China.
  • 2 Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
  • 3 Department of Obstetrics and Gynecology, Chongqing Health Center for Women and Children (Women and Children's Hospital of Chongqing Medical University), Chongqing 401120, China.
  • 4 Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Department of Obstetrics and Gynecology, Chongqing Health Center for Women and Children (Women and Children's Hospital of Chongqing Medical University), Chongqing 401120, China.
  • 5 Guizhou University Medical College, Guiyang 550025, Guizhou Province, China; Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
  • 6 Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China. Electronic address: yaoqi_wh@163.com.
PMID: 39756501 DOI: 10.1016/j.cellsig.2024.111583
Abstract

Acute Myeloid Leukemia (AML) are challenging blood cancers with limited long-term survival rates, necessitating novel therapeutic strategies. This study explored the role of Histone deacetylase (HDAC) inhibitors in enhancing Ferroptosis in AML cells by modulating iron metabolism. We demonstrated that HDAC inhibitors (Entinostat and Vorinostat) sensitize AML cells to Ferroptosis both in vitro and in vivo. Mechanistically, we show that HDAC Inhibitor treatment upregulated the expression of iron metabolism genes that lead to increased labile iron pool. Notably, NCOA4, a ferritin degradation mediator, and HMOX1/2 proteins, involved in heme breakdown, were identified as critical contributors to this process. The functional role of these genes was confirmed through CRISPR-Cas9 mediated knockouts, which significantly rescued cells from HDAC-induced Ferroptosis sensitivity. Our results suggest a novel therapeutic approach for AML, where combining HDAC inhibitors with Ferroptosis inducers could exploit the disrupted iron metabolism in AML cells. This study highlights the potential of HDAC inhibitors to modulate iron metabolism pathways, offering new insights into the treatment of these malignancies.

Keywords

AML; Ferroptosis; HDAC inhibitors; Iron metabolism.

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