ORIGINAL RESEARCH article
Front. Med.
Sec. Gastroenterology
Volume 12 - 2025 | doi: 10.3389/fmed.2025.1592116
This article is part of the Research TopicMetabolism at the Crossroads of DNA Repair, Immune Response, and Tumor Microenvironment in RadiotherapyView all 3 articles
Carbon-ion radiotherapy induces ferroptosis and M1 macrophage polarization to inhibit the development of gastric cancer by downregulating DHODH
Provisionally accepted
Yue Wang*
Hongyi Cai- Gansu University of Chinese Medicine, Lanzhou, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Background: Carbon-ion radiotherapy (CIRT) is an advanced form of high linear energy transfer (LET) radiotherapy that has demonstrated superior biological effectiveness compared to conventional photon therapy in the treatment of various malignancies, however, its role in gastric cancer remains unclear. Dihydroorotate dehydrogenase (DHODH), a key enzyme implicated in cancer progression, has been linked to tumor radiosensitivity. This study aims to investigate whether CIRT inhibits gastric cancer progression via the regulation of DHODH. Methods: Human gastric cancer cell lines (HGC27, AGS) were treated with carbon-ion radiotherapy (CIRT; 0, 2, and 4 Gy). Cell viability, migration, and invasion were assessed by MTT and transwell assays. Expression of ferroptosis-related markers and DHODH (dihydroorotate dehydrogenase) was evaluated using Western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Macrophage polarization was assessed by flow cytometry after exposure to tumor-conditioned medium (CM). BALB/c nude mice were subcutaneously injected with AGS cells and randomly assigned to control, CIRT, and DHODH+CIRT groups. Results: In vitro, CIRT suppressed DHODH expression and enhanced intracellular iron and reactive oxygen species (ROS) accumulation, promoting ferroptosis in gastric cancer cells. CM from irradiated cells increased the CD86⁺CD206⁻ macrophage population and upregulated M1-associated cytokines. In vivo, CIRT significantly reduced tumor growth in xenograft models, and this effect was attenuated by DHODH overexpression. Tumor tissues from the CIRT group exhibited increased ferroptosis marker ACSL4 and reduced GPX4 expression, consistent with in vitro findings. Conclusion: These findings suggest that CIRT promotes ferroptosis and drives M1-like macrophage polarization through DHODH suppression. Targeting DHODH may enhance the therapeutic efficacy of CIRT in gastric cancer.
Keywords: gastric cancer, CIRT, DHODH, Macrophages, ferroptosis
Received: 12 Mar 2025; Accepted: 07 Aug 2025.
Copyright: © 2025 Wang and Cai. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Yue Wang, Gansu University of Chinese Medicine, Lanzhou, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.