Journal of Zhejiang University SCIENCE  B

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


Author(s):  Xiaoqian WANG1, Minghui XIU1, 2, Linghui CHANG1, Jinhan WU2, Yan WANG2, Jianzheng HE1, 3, 4, Yongqi LIU2, 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 XIU1,2, Linghui CHANG1, Jinhan WU2, Yan WANG2, Jianzheng HE1,3,4, Yongqi LIU2,3. 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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year="in press",
publisher="Zhejiang University Press & Springer",
doi="https://doi.org/10.1631/jzus.B2500346"
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%A Yongqi LIU2
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doi="https://doi.org/10.1631/jzus.B2500346"

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A1 - Linghui CHANG1
A1 - Jinhan WU2
A1 - Yan WANG2
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doi="https://doi.org/10.1631/jzus.B2500346"


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.

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

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On-line Access: 2025-11-04

Received: 2025-07-07

Revision Accepted: 2025-09-22

Crosschecked: 0000-00-00

Cited: 0

Clicked: 1226

Citations:  Bibtex RefMan EndNote GB/T7714

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