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Background <p>Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy with poor overall survival (OS). Resistance to chemotherapeutic drugs such as idarubicin (IDA) remains a major cause of treatment failure. This study investigated the anti-leukemic activity of halofuginone (HF) a synthetic derivative of the natural compound from hydrangea Dichroa febrifuge and its potential to overcome IDA resistance in AML cells.</p> Methods <p>Apoptosis, proliferation, cell cycle, and colony formation were assessed in AML cells treated with HF. RNA sequencing (RNA-seq) was performed to identify the potential molecular targets of HF. The anti-leukemic efficacy of HF was further assessed in NOD/SCID-IL2Rγ (NSG) mice xenografted with human relapsed/refractory (R/R) AML samples.</p> Results <p>HF treatment significantly inhibited cell proliferation, reduced colony formation, and induced apoptosis in AML cells. By RNA-seq analysis, S100A8 and S100A9 (S100A8/A9) were identified as potential targets of HF, and HF treatment markedly suppressed their expression. Overexpression of S100A8/A9 abrogated the anti-leukemic effects of HF, indicating that S100A8/A9 are critical mediators of HF activity. Mechanistically, HF activated the amino acid starvation response (AAR), leading to phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (p-eIF2α), subsequent downregulation of S100A8/A9, and elevation of cytoplasmic Ca<sup>2</sup>⁺ levels. Knockdown of eIF2α prevented HF-induced downregulation of S100A8/A9, confirming that HF regulates S100A8/A9 expression via the eIF2α pathway. Furthermore, HF treatment inhibited global protein synthesis, enhanced the cytotoxicity of chemotherapeutic drugs, and reversed IDA resistance by suppressing S100A8/A9 expression. Finally, HF inhibits leukemic infiltration and extended OS in MLL-AF9-transduced AML mice and enhanced IDA-induced anti-leukemic effects in R/R AML-xenografted NSG mice model.</p> Conclusions <p>These findings reveal that HF exerts anti-leukemic effects by modulating the p-eIF2α–S100A8/A9–Ca<sup>2</sup>⁺ signaling axis in AML cells. HF represents a promising therapeutic candidate for AML, particularly for patients with IDA-resistant disease.</p>

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Halofuginone exerts broad-spectrum cytotoxic effects by regulating p-eIF2α-S100A8/A9-calcium signaling, inhibiting global protein synthesis, and reversing the resistance of idarubicin in acute myeloid leukemia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月6日

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  • Liuzhi Shi,
  • Min Zhao,
  • Chen Meng,
  • Min Li,
  • Xuanyu Yu,
  • Shixin Zhang,
  • Shirui Yu,
  • Xinyao Chen,
  • Bin Zhou,
  • Chongyun Xing,
  • Jinjun Jia,
  • Jingying Zhou,
  • Shenmeng Gao

摘要

Background

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy with poor overall survival (OS). Resistance to chemotherapeutic drugs such as idarubicin (IDA) remains a major cause of treatment failure. This study investigated the anti-leukemic activity of halofuginone (HF) a synthetic derivative of the natural compound from hydrangea Dichroa febrifuge and its potential to overcome IDA resistance in AML cells.

Methods

Apoptosis, proliferation, cell cycle, and colony formation were assessed in AML cells treated with HF. RNA sequencing (RNA-seq) was performed to identify the potential molecular targets of HF. The anti-leukemic efficacy of HF was further assessed in NOD/SCID-IL2Rγ (NSG) mice xenografted with human relapsed/refractory (R/R) AML samples.

Results

HF treatment significantly inhibited cell proliferation, reduced colony formation, and induced apoptosis in AML cells. By RNA-seq analysis, S100A8 and S100A9 (S100A8/A9) were identified as potential targets of HF, and HF treatment markedly suppressed their expression. Overexpression of S100A8/A9 abrogated the anti-leukemic effects of HF, indicating that S100A8/A9 are critical mediators of HF activity. Mechanistically, HF activated the amino acid starvation response (AAR), leading to phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (p-eIF2α), subsequent downregulation of S100A8/A9, and elevation of cytoplasmic Ca2⁺ levels. Knockdown of eIF2α prevented HF-induced downregulation of S100A8/A9, confirming that HF regulates S100A8/A9 expression via the eIF2α pathway. Furthermore, HF treatment inhibited global protein synthesis, enhanced the cytotoxicity of chemotherapeutic drugs, and reversed IDA resistance by suppressing S100A8/A9 expression. Finally, HF inhibits leukemic infiltration and extended OS in MLL-AF9-transduced AML mice and enhanced IDA-induced anti-leukemic effects in R/R AML-xenografted NSG mice model.

Conclusions

These findings reveal that HF exerts anti-leukemic effects by modulating the p-eIF2α–S100A8/A9–Ca2⁺ signaling axis in AML cells. HF represents a promising therapeutic candidate for AML, particularly for patients with IDA-resistant disease.