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<p><i>Helicobacter pylori</i> (<i>H. pylori</i>), one of the main predisposing factors for the development of gastric cancer (GC), is a key factor affecting intracellular ROS and iron metabolism. Ferroptosis is characterized by iron-dependent regulated cell death resulting from excessive lipid peroxidation and is a significant process in this context. Nevertheless, the intricate relationship between <i>H. pylori</i> and ferroptosis remains elusive. In this study, we find a suppressive effect of <i>H. pylori</i> on ferroptosis. Specifically, <i>H. pylori</i> inhibits RSL3/Erastin-induced ferroptosis in GC cells via Vacuolating cytotoxin A (VacA). Mechanistically, VacA binds to p62 and KEAP1, disrupting their interaction and preventing KEAP1 degradation. This stabilization of KEAP1 inhibits NRF2 nuclear translocation and subsequently suppresses HMOX1 transcription, leading to reduced Fe<sup>2+</sup> accumulation and inhibition of ferroptosis. Additionally, cisplatin induces ferroptosis in GC cells, and HMOX1 overexpression further enhances its cytotoxic effect. Finally, we identify that Hemin (an HMOX1 inducer) enhances the antitumor effect of cisplatin in both a cell line-derived xenograft gastric cancer model and a <i>H. pylori</i>-induced murine gastric cancer model. These findings unveil a previously unrecognized role of <i>H. pylori</i> in conferring resistance to ferroptosis and identify HMOX1 as a potential therapeutic target for <i>H. pylori</i>-associated GC.</p>

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Helicobacter pylori VacA suppresses HMOX1-driven ferroptosis via the KEAP1/NRF2 axis in gastric cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月28日

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  • Yixian Guo,
  • Jinnan Chen,
  • Yu Huang,
  • Yaqin Yuan,
  • Jieqiong Chen,
  • Shuhan Qiu,
  • Shouyu Ke,
  • Zeyu Wang,
  • Feng Xie,
  • Danhua Xu,
  • Bin Li,
  • Hong Lu,
  • Xiao Liang

摘要

Helicobacter pylori (H. pylori), one of the main predisposing factors for the development of gastric cancer (GC), is a key factor affecting intracellular ROS and iron metabolism. Ferroptosis is characterized by iron-dependent regulated cell death resulting from excessive lipid peroxidation and is a significant process in this context. Nevertheless, the intricate relationship between H. pylori and ferroptosis remains elusive. In this study, we find a suppressive effect of H. pylori on ferroptosis. Specifically, H. pylori inhibits RSL3/Erastin-induced ferroptosis in GC cells via Vacuolating cytotoxin A (VacA). Mechanistically, VacA binds to p62 and KEAP1, disrupting their interaction and preventing KEAP1 degradation. This stabilization of KEAP1 inhibits NRF2 nuclear translocation and subsequently suppresses HMOX1 transcription, leading to reduced Fe2+ accumulation and inhibition of ferroptosis. Additionally, cisplatin induces ferroptosis in GC cells, and HMOX1 overexpression further enhances its cytotoxic effect. Finally, we identify that Hemin (an HMOX1 inducer) enhances the antitumor effect of cisplatin in both a cell line-derived xenograft gastric cancer model and a H. pylori-induced murine gastric cancer model. These findings unveil a previously unrecognized role of H. pylori in conferring resistance to ferroptosis and identify HMOX1 as a potential therapeutic target for H. pylori-associated GC.