JZUS - Journal of Zhejiang University SCIENCE

Journal of Zhejiang University SCIENCE B

Accepted manuscript available online (unedited version)

5-Fluorouracil causes intestinal damage via gut microbiota-mediated ferroptosis and innate immunity in Drosophila melanogaster and mice

Author(s): Xiaoqian WANG¹, Minghui XIU^1, ², Linghui CHANG¹, Jinhan WU², Yan WANG², Jianzheng HE^1, ^3, ⁴, Yongqi LIU^2, ³
Affiliation(s): ¹Provincial-level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and University, Gansu University of Chinese Medicine, Lanzhou 730000, China ²College of Public Health, Gansu University of Chinese Medicine, Lanzhou 730000, China ³Key Laboratory of Dunhuang Medicine, Ministry of Education, Lanzhou 730000, China ⁴NHC Key Laboratory for Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou 730000, China
Corresponding email(s): Jianzheng HE, hejianzheng1006@163.com Yongqi LIU, liuyongqi73@163.com
Key Words: Intestine mucositis; 5-Fluorouracil (5-FU); Gut microbiota; Ferroptosis; Drosophila melanogaster

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Xiaoqian WANG¹, Minghui XIU^1,², Linghui CHANG¹, Jinhan WU², Yan WANG², Jianzheng HE^1,^3,⁴, Yongqi LIU^2,³. 5-Fluorouracil causes intestinal damage via gut microbiota-mediated ferroptosis and innate immunity in Drosophila melanogaster and mice[J]. Journal of Zhejiang University Science B,in press.Frontiers of Information Technology & Electronic Engineering,in press.https://doi.org/10.1631/jzus.B2500346

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author="Xiaoqian WANG¹, Minghui XIU^1,², Linghui CHANG¹, Jinhan WU², Yan WANG², Jianzheng HE^1,^3,⁴, Yongqi LIU^2,³",
journal="Journal of Zhejiang University Science B",
year="in press",
publisher="Zhejiang University Press & Springer",
doi="https://doi.org/10.1631/jzus.B2500346"
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Abstract
Chinese Summary
Academic Network
Reviewer Comment

Abstract: Chemotherapy-induced intestinal mucositis (IM) severely impacts cancer prognosis, yet effective therapies remain limited due to unclear mechanisms. This study aimed to establish a 5-fluorouracil (5-FU)-induced IM model in Drosophila melanogaster (flies). The results revealed that 5-FU caused systemic and intestinal damage in flies, including reduced survival rate, starvation resistance, development, excretion, crop motility and intestinal length; disrupted acid-base homeostasis; and increased enterocyte death. The combined analysis of transcriptomics, bioinformatics, and microbiomics demonstrated that intestinal damage induced by 5-FU was associated with gut microbiota imbalance, ferroptosis, and innate immunity. 5-FU consistently activated ferroptosis in flies, including increased reactive oxygen species (ROS), malondialdehyde (MDA), total Fe2?, lipid peroxidation, and the expression of key ferroptosis-related genes. Ferroptosis inhibitor improved survival rates and intestinal damage in 5-FU-treated flies. Furthermore, antibiotic depletion of gut microbiota alleviated intestinal damage and down-regulated innate immune and ferroptosis markers in 5-FU-induced flies. Conversely, fecal microbiota transplantation (FMT) from 5-FU-induced flies was sufficient to recapitulate intestinal injury in healthy flies. 5-FU also consistently induced intestinal damage and ferroptosis in mice, including increased ROS, ACSL4, and 4-HNE levels, and decreased GPX4. This study implicates gut microbiota-driven ferroptosis and innate immunity in 5-FU-induced IM, establishing Drosophila melanogaster as a powerful model for mechanistic discovery and drug screening.

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