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Purpose <p>To investigate the unexplored therapeutic potential and identify the specific molecular targets of homoharringtonine (HHT) in gastric cancer (GC).</p> Methods <p>HHT’s efficacy was evaluated in GC cell lines (MKN1/MKN45), normal epithelial cells (GES-1), and an HGC27 xenograft model. Mechanisms were investigated using RNA-sequencing, microscale thermophoresis (MST), molecular docking, and biochemical assays.</p> Results <p>HHT suppressed GC cell proliferation and migration, inducing G1-phase arrest and apoptosis, while demonstrating lower cytotoxicity toward normal GES-1 cells. MST and docking assays confirmed that HHT directly and stably binds to AKT (<i>K</i><sub><i>D</i></sub>= 6.496 nM) and suppresses the PI3K/AKT/FOXO/GSK3β signaling pathway. Concurrently, transcriptomic profiling and experimental validation showed that HHT disrupts glutathione metabolism. It depleted intracellular GSH and downregulated GPX4, triggering ferroptosis-like oxidative damage and mitochondrial cristae loss. In vivo, HHT inhibited GC xenograft tumor growth without causing systemic toxicity, which was accompanied by decreased Ki-67 and increased Caspase-3 expression.</p> Conclusion <p>HHT inhibits GC progression by suppressing AKT-mediated tumor growth and inducing GPX4-dependent ferroptosis. These findings highlight HHT as a promising targeted therapeutic for GC.</p>

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Homoharringtonine suppresses gastric cancer progression by targeting PI3K/ AKT/FOXO pathway and impairing the GSH–GPX4 antioxidant axis

  • 期刊论文

  • 发表日期：

    2026年4月29日

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  • Xiaonan Wang,
  • Xiao Ying,
  • Sunyuan Lv,
  • Shanshan Ru,
  • Haonan Jin,
  • Yingzhe Zhang,
  • Jingjing Guo

摘要

Purpose

To investigate the unexplored therapeutic potential and identify the specific molecular targets of homoharringtonine (HHT) in gastric cancer (GC).

Methods

HHT’s efficacy was evaluated in GC cell lines (MKN1/MKN45), normal epithelial cells (GES-1), and an HGC27 xenograft model. Mechanisms were investigated using RNA-sequencing, microscale thermophoresis (MST), molecular docking, and biochemical assays.

Results

HHT suppressed GC cell proliferation and migration, inducing G1-phase arrest and apoptosis, while demonstrating lower cytotoxicity toward normal GES-1 cells. MST and docking assays confirmed that HHT directly and stably binds to AKT (KD= 6.496 nM) and suppresses the PI3K/AKT/FOXO/GSK3β signaling pathway. Concurrently, transcriptomic profiling and experimental validation showed that HHT disrupts glutathione metabolism. It depleted intracellular GSH and downregulated GPX4, triggering ferroptosis-like oxidative damage and mitochondrial cristae loss. In vivo, HHT inhibited GC xenograft tumor growth without causing systemic toxicity, which was accompanied by decreased Ki-67 and increased Caspase-3 expression.

Conclusion

HHT inhibits GC progression by suppressing AKT-mediated tumor growth and inducing GPX4-dependent ferroptosis. These findings highlight HHT as a promising targeted therapeutic for GC.