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  3. Exosomal CagA induces macrophage polarization and ferroptosis by JAK1-2/STAT1 signaling pathway in Helicobacter pylori-associated gastritis

Exosomal CagA induces macrophage polarization and ferroptosis by JAK1-2/STAT1 signaling pathway in Helicobacter pylori-associated gastritis

  • Free Radic Biol Med. 2025 Nov:239:91-103. doi: 10.1016/j.freeradbiomed.2025.07.031.
Jiahui Lin 1,  Wei Lu 2,  Sha Cheng 2,  Zonghao Zhang 3,  Yanan Hu 4,  Shuyue Chen 5,  Huan Li 2,  Jingshu Chi 2,  Xiaoming Liu 6,  Yinjie Guo 7,  Canxia Xu 8
Affiliations

Affiliations

  • 1 Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, 410013, China; Department of Gastroenterology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
  • 2 Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, 410013, China.
  • 3 School and Hospital of Stomatology, Fujian Medical University, Fujian, 350000, China.
  • 4 Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
  • 5 Department of Plastic and Reconstruction, Third Xiangya Hospital of Central South University, Changsha, 410013, China.
  • 6 Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, 410013, China. Electronic address: liuxiaoming26@csu.edu.cn.
  • 7 Eye Center of Xiangya Hospital, Central South University, Changsha, Hunan. 410008, China; Hunan Key Laboratory of Ophthalmology, Central South University, Changsha, Hunan, 410008, China. Electronic address: 22022240@csu.edu.cn.
  • 8 Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, 410013, China. Electronic address: xucanxia2000@163.com.
PMID: 40706822 DOI: 10.1016/j.freeradbiomed.2025.07.031
Abstract

Helicobacter pylori (H. pylori) Infection is a major cause of gastric diseases, with the virulence factor CagA carried by exosomes playing a crucial role in regulating inflammation. Ferroptosis and M1 polarization are key mechanisms in promoting inflammation, yet the role of CagA in inducing macrophage Ferroptosis and M1 polarization to exacerbate gastric mucosal inflammation remains unclear.In this study, CagA-positive (CagA+) and CagA-negative (CagA-) H. pylori strains were co-cultured with gastric epithelial cells, and exosomes were isolated to assess their impact on macrophage polarization and Ferroptosis markers. We found that exosomal CagA induces M1 polarization and Ferroptosis in macrophages by activating the JAK/STAT1 signaling pathway. The Ferroptosis inhibitor SLC7A11 plays a key role in CagA-induced Ferroptosis. Furthermore, exosomal CagA enhances STAT1 nuclear expression, which binds to the SLC7A11 promoter, downregulating its expression. In biopsies from CagA + H. pylori-infected gastritis patients, increased iNOS levels and reduced SLC7A11 expression were observed. Our findings indicate that exosomal CagA promotes macrophage M1 polarization and Ferroptosis through the JAK/STAT1 signaling pathway. This study provides new insights and potential therapeutic targets for H. pylori-associated gastritis.

Keywords

CagA; Exosomes; Ferroptosis; Gastritis; Helicobacter pylori; Macrophage polarization.

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