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NEDD4L mediates intestinal epithelial cell ferroptosis to restrict inflammatory bowel diseases and colorectal tumorigenesis
Jingjing Liang, … , Xiaojian Wang, Wenlong Lin
Jingjing Liang, … , Xiaojian Wang, Wenlong Lin
Published December 17, 2024
Citation Information: J Clin Invest. 2025;135(3):e173994. https://doi.org/10.1172/JCI173994.
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Research Article Cell biology Inflammation Article has an altmetric score of 8

NEDD4L mediates intestinal epithelial cell ferroptosis to restrict inflammatory bowel diseases and colorectal tumorigenesis

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Abstract

Various factors play key roles in maintaining intestine homeostasis. Disruption of the balance may lead to inflammatory bowel diseases and even colorectal cancer (CRC). Loss or gain of function of many key proteins can result in dysregulated intestinal homeostasis. Our research demonstrated that neural precursor cells expressed developmentally downregulated 4–like protein (NEDD4L, or NEDD4-2), a type of HECT family E3 ubiquitin ligase, played an important role in maintaining intestinal homeostasis. NEDD4L expression was significantly inhibited in intestinal epithelial cells (IECs) of patients with Crohn’s disease, ulcerative colitis, and CRC. Global KO of NEDD4L or its deficiency in IECs exacerbated colitis induced by dextran sulfate sodium (DSS) and 2,4,6-trinitrobenzene sulfonic acid (TNBS) and CRC induced by azoxymethane and DSS. Mechanistically, NEDD4L deficiency in IECs inhibited expression of the key ferroptosis regulator glutathione peroxidase 4 (GPX4) by reducing the protein expression of solute carrier family 3 member 2 (SLC3A2) without affecting its gene expression, ultimately promoting DSS-induced IEC ferroptosis. Importantly, ferroptosis inhibitors reduced the susceptibility of NEDD4L-deficient mice to colitis and colitis-associated CRC. Thus, NEDD4L is an important regulator in IEC ferroptosis, maintaining intestinal homeostasis, making it a potential clinical target for diagnosing and treating IBDs.

Authors

Jingjing Liang, Ning Wang, Yihan Yao, Yingmei Wang, Xiang An, Haofei Wang, Huan Liu, Yu Jiang, Hui Li, Xiaoqing Cheng, Jiaqi Xu, Xiaojing Liang, Jun Lou, Zengfeng Xin, Ting Zhang, Xiaojian Wang, Wenlong Lin

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Figure 1

NEDD4L expression is significantly downregulated in IECs of patients with IBDs.

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NEDD4L expression is significantly downregulated in IECs of patients wit...
(A and B) Statistical analysis of NEDD4L immunohistochemical (IHC) intensity in the biopsies from Xijing Hospital (cohort 1) (A) and representative IHC staining of sections traced with anti-NEDD4L antibody (B). Normal control (HC) n = 40 and UC n = 83. Scale bars: 50 μm. (C and D) Statistical analysis of NEDD4L IHC intensity in the biopsies from the First Affiliated Hospital of Zhejiang University School of Medicine (cohort 2) (C) and representative IHC staining of sections (D). Normal control (HC) n = 31, UC n = 36, and CD n = 41. Scale bars: 50 μm. (E and F) Statistical analysis of NEDD4L IHC intensity in the biopsies with disease status record from cohort 2 (E) and representative IHC staining of sections traced with anti-NEDD4L antibody (F). Mild n = 14 and moderate/severe n = 48. Scale bars: 50 μm. (G and H) Quantitative PCR (qPCR) analysis (G) and representative Western blotting (H) of NEDD4L in the mucosa from patients with IBDs and their corresponding normal tissues (n = 24 per group). (I and J) Western blotting analysis (I) and protein intensity analysis (J) according to I using ImageJ software (NIH) of NEDD4L from the IECs of the WT mice treated or not treated with DSS for 4 days (n = 5 per group). Red arrows indicate NEDD4L expression in IECs, and green arrows indicate NEDD4L expression in non-IECs. Data represent mean ± SEM. Each dot represents an independent sample. **P < 0.01; ***P < 0.001; ****P < 0.0001. Statistical analysis was performed using 1-way ANOVA with multiple comparisons in C, and a 2-tailed Student’s t test in A, E, G, and J.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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