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.
View: Text | PDF
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

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

×

Figure 2

Nedd4l deficiency in mice promotes DSS-induced experimental colitis in a non-hematopoietic cell–dependent manner.

Options: View larger image (or click on image) Download as PowerPoint
Nedd4l deficiency in mice promotes DSS-induced experimental colitis in ...
(A) Nedd4l-global-deficient mice (Nedd4l+/–) and control littermates (Nedd4l+/+) were given 4% DSS for 5 days followed by water to induce acute colitis. Mouse death was monitored until day 9. n = 20 per group. (B–F) Nedd4l+/– and Nedd4l+/+ mice were given 3% DSS for 5 days followed by water until day 9. n = 9 per group. Body weight change (B), bleeding scores (C), colon length (D), gross morphology images (E), and H&E staining of colons (F) from Nedd4l+/+ and Nedd4l+/– mice are shown. Red arrows point to epithelial degeneration and green arrows to inflammatory infiltrates. Scale bars: 200 μm or 50 μm (amplified sections). (G–J) Bone marrow from Nedd4l+/+ (WT) and Nedd4l–/– (KO) mice was transferred to WT (n = 7) and KO (n = 10) mice to generate bone marrow reconstitution mice. The bone marrow reconstitution mice were subjected to 3% DSS treatment for 5 days followed by water, and mouse death (G) and body weight changes (H) were monitored until day 9. (I and J) From a separate experiment, colon length (I) and gross morphology images (J) of colons from mice on day 6 after DSS treatment. n = 4 per group. Data represent mean ± SEM from at least 2 independent experiments. Each dot represents an independent sample. **P < 0.01; ****P < 0.0001. Statistical analysis was performed using a log-rank test in A and G, a 2-way ANOVA test in B, C, and H, and a 2-tailed Student’s t test in D and I.