Various factors play key roles in maintaining intestine homeostasis. Disruption of the balance may lead to intestinal inflammatory diseases (IBDs) 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 down-regulated 4-like protein, NEDD4L (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 (CD), ulcerative colitis (UC), and CRC. Global knockout of NEDD4L or its deficiency in IECs exacerbated dextran sulfate sodium (DSS)-/2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis and azoxymethane (AOM)/DSS-induced colorectal cancer. Mechanistically, NEDD4L deficiency in IECs inhibited the key ferroptosis regulator glutathione peroxidase 4 (GPX4) expression 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 colorectal cancer (CAC). Thus, NEDD4L was an important regulator in IEC ferroptosis, maintaining intestinal homeostasis, making it a potential clinical target for diagnosing and treating IBDs.

中文翻译：

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NEDD4L 介导肠上皮细胞铁死亡，以限制炎症性肠病和结直肠肿瘤发生。


各种因素在维持肠道稳态中起着关键作用。平衡的破坏可能导致肠道炎症性疾病 （IBD） 甚至结直肠癌 （CRC）。许多关键蛋白的功能丧失或增加会导致肠道稳态失调。我们的研究表明，神经前体细胞表达发育下调的 4 样蛋白 NEDD4L （NEDD4-2），一种 HECT 家族 E3 泛素连接酶，在维持肠道稳态中起重要作用。NEDD4L 在克罗恩病 （CD） 、溃疡性结肠炎 （UC） 和 CRC 患者的肠上皮细胞 （IECs） 中表达受到显著抑制。NEDD4L 的整体敲除或其在 IEC 中的缺陷加剧了葡聚糖硫酸钠 （DSS）-/2,4,6-三硝基苯磺酸 （TNBS） 诱导的结肠炎和嘧氧甲烷 （AOM）/DSS 诱导的结直肠癌。从机制上讲，IECs 中的 NEDD4L 缺陷通过降低溶质载体家族 3 成员 2 （SLC3A2） 的蛋白表达来抑制关键的铁死亡调节因子谷胱甘肽过氧化物酶 4 （GPX4） 表达而不影响其基因表达，最终促进 DSS 诱导的 IEC 铁死亡。重要的是，铁死亡抑制剂降低了 NEDD4L 缺陷小鼠对结肠炎和结肠炎相关结直肠癌 （CAC） 的易感性。因此，NEDD4L 是 IEC 铁死亡的重要调节因子，维持肠道稳态，使其成为诊断和治疗 IBD 的潜在临床靶点。