RIP3 regulates doxorubicin-induced intestinal mucositis via FUT2-mediated α-1,2-fucosylation

Wei Wen; Xiaomin Hu; Jialin Liu; Fanxin Zeng; Yihua Xu; Ye Yuan; Chunyan Gao; Xueting Sun; Bo Cheng; Jue Wang; Xinli Hu; Rui-Ping Xiao; Xing Chen; Xiuqin Zhang

doi:10.1007/s00011-024-01932-2

RIP3 regulates doxorubicin-induced intestinal mucositis via FUT2-mediated α-1,2-fucosylation

Inflamm Res. 2024 Oct;73(10):1781-1801. doi: 10.1007/s00011-024-01932-2. Epub 2024 Aug 24.

Authors

Wei Wen^#^{1

2

3}, Xiaomin Hu^#^{1

2

4}, Jialin Liu^#^{5

6}, Fanxin Zeng^#^{1

2

7}, Yihua Xu^#^{1

2}, Ye Yuan^{1

2}, Chunyan Gao^{1

2}, Xueting Sun^{1

2}, Bo Cheng^{5

6}, Jue Wang^{1

2}, Xinli Hu^{1

2}, Rui-Ping Xiao^{8

9

10

11

12}, Xing Chen^{13

14

15

16

17}, Xiuqin Zhang^{18

19

20

21}

Affiliations

¹ Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, 100871, China.
² Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 100871, China.
³ PKU-Nanjing Institute of Translational Medicine, Nanjing, 211800, China.
⁴ State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China.
⁵ College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China.
⁶ Beijing National Laboratory for Molecular Sciences, Peking University, Beijing, 100871, China.
⁷ Department of Clinical Research Center, Dazhou Central Hospital, Dazhou, 635000, China.
⁸ Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, 100871, China. [email protected].
⁹ Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 100871, China. [email protected].
¹⁰ PKU-Nanjing Institute of Translational Medicine, Nanjing, 211800, China. [email protected].
¹¹ State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, 100871, China. [email protected].
¹² Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China. [email protected].
¹³ College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China. [email protected].
¹⁴ Beijing National Laboratory for Molecular Sciences, Peking University, Beijing, 100871, China. [email protected].
¹⁵ Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China. [email protected].
¹⁶ Synthetic and Functional Biomolecules Center, Peking University, Beijing, 100871, China. [email protected].
¹⁷ Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Peking University, Beijing, 100871, China. [email protected].
¹⁸ Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, 100871, China. [email protected].
¹⁹ Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 100871, China. [email protected].
²⁰ PKU-Nanjing Institute of Translational Medicine, Nanjing, 211800, China. [email protected].
²¹ National Biomedical Imaging Center, School of Future Technology, Peking University, Beijing, 100871, China. [email protected].

^# Contributed equally.

PMID: 39180691
DOI: 10.1007/s00011-024-01932-2

Abstract

Objective: Intestinal mucositis is one of the common side effects of anti-cancer chemotherapy. However, the molecular mechanisms involved in mucositis development remain incompletely understood. In this study, we investigated the function of receptor-interacting protein kinase 3 (RIP3/RIPK3) in regulating doxorubicin-induced intestinal mucositis and its potential mechanisms.

Methods: Intestinal mucositis animal models were induced in mice for in vivo studies. Rat intestinal cell line IEC-6 was used for in vitro studies. RNA‑seq was used to explore the transcriptomic changes in doxorubicin-induced intestinal mucositis. Intact glycopeptide characterization using mass spectrometry was applied to identify α-1,2-fucosylated proteins associated with mucositis.

Results: Doxorubicin treatment increased RIP3 expression in the intestine and caused severe intestinal mucositis in the mice, depletion of RIP3 abolished doxorubicin-induced intestinal mucositis. RIP3-mediated doxorubicin-induced mucositis did not depend on mixed lineage kinase domain-like (MLKL) but on α-1,2-fucosyltransferase 2 (FUT2)-catalyzed α-1,2-fucosylation on inflammation-related proteins. Deficiency of MLKL did not affect intestinal mucositis, whereas inhibition of α-1,2-fucosylation by 2-deoxy-D-galactose (2dGal) profoundly attenuated doxorubicin-induced inflammation and mucositis.

Conclusions: RIP3-FUT2 pathway is a central node in doxorubicin-induced intestinal mucositis. Targeting intestinal RIP3 and/or FUT2-mediated α-1,2-fucosylation may provide potential targets for preventing chemotherapy-induced intestinal mucositis.

Keywords: Doxorubicin; FUT2; Intestinal mucositis; RIP3; Α-1,2-fucosylation.

MeSH terms

Animals
Antibiotics, Antineoplastic / adverse effects
Antibiotics, Antineoplastic / toxicity
Cell Line
Doxorubicin* / adverse effects
Fucosyltransferases* / genetics
Fucosyltransferases* / metabolism
Galactoside 2-alpha-L-fucosyltransferase*
Intestinal Mucosa / drug effects
Intestinal Mucosa / metabolism
Intestinal Mucosa / pathology
Male
Mice
Mice, Inbred C57BL*
Mice, Knockout
Mucositis* / chemically induced
Mucositis* / metabolism
Mucositis* / pathology
Rats
Receptor-Interacting Protein Serine-Threonine Kinases* / genetics
Receptor-Interacting Protein Serine-Threonine Kinases* / metabolism

Substances

Doxorubicin
Receptor-Interacting Protein Serine-Threonine Kinases
Fucosyltransferases
Galactoside 2-alpha-L-fucosyltransferase
Ripk3 protein, mouse
Antibiotics, Antineoplastic

Abstract

MeSH terms

Substances

Grants and funding