许多主食中都含有可检测到的黄曲霉毒素和赭曲霉毒素 A (OTA) 等霉菌毒素；人们对长期接触此类毒素对健康的影响知之甚少。越来越多的证据证实了 OTA 在上调氧化应激和炎症反应引起的组织损伤中的重要作用。然而，赭曲霉毒素A是否可以促进慢性结肠炎及其相关结肠癌（CRC）的发展以及潜在的分子机制仍不清楚。此外，RING 指与 C 激酶相互作用的蛋白 (RINCK) 是一种泛素连接酶，可介导免疫反应。不幸的是，RINCK调节结肠炎的潜在分子功能仍然很大程度上未知。本研究旨在通过靶向核因子红细胞2相关因子，提供RICK在结肠炎和早期结直肠癌进展中的作用机制证据，以响应OTA治疗2 (NRF2)。这项工作使用了癌症基因组图谱 (TCGA) 数据库、GEO 数据库、具有 CC 表型的人类受试者和 CC 细胞系。通过生物信息分析、临床实验、RNA-seq和验证实验等综合手段揭示了OTA、RINCK与CC治疗之间的病理联系。在本研究中，在结肠炎环境下的氧化应激下，我们首先确定了RINCK作为RINCK 是核因子红细胞 2 相关因子 2 (NRF2) 的关键调节因子和新型内源性抑制因子，我们还证实 RINCK 是 NRF2 伙伴蛋白，可催化其在肠上皮细胞 (IEC) 中的泛素化和降解。值得注意的是，在体内研究中，OTA 预处理引发的病理表型，以及右旋糖酐硫酸钠 (DSS) 诱导的结肠炎的后处理，因 Rinck、IEC-Rinck(KO) 和腺病毒相关病毒的 IEC 特异性缺陷而显着减轻在啮齿类动物模型中，AAV（AAV）触发的 Rinck 抑制，以及兔模型中慢病毒（LV）介导的 Rinck 下调（LV-shRinck），通过内源性活性氧（ROS）产生、促炎细胞因子含量的减少来确定。改善体重、降低存活率、恢复结肠长度、缓解 DAI 和组织学评分。相反，通过IEC特异性Rinck过度表达的转基因小鼠，IEC-Rinck(OE)在急性或慢性结肠炎啮齿动物模型和体外实验中加速结肠炎。此外，我们发现IEC-Rinck（KO）也显着减少了OTA预处理促进的氧化偶氮甲烷（AOM）/DSS诱导的结肠炎相关的早期结直肠癌（CRC），肿瘤数量和相应KI-67水平的减少表明。临床样本分析显示，CRC表型患者的肿瘤组织中RINCK水平大幅升高。与此同时，RINCK 缺失分别显着延缓了体外和体内结肠癌的增殖和肿瘤生长。从机制上讲，为了应对结肠炎的发作，RINCK直接与NRF2相互作用，并通过增加K48连接泛素链促进泛素蛋白酶体降解，从而导致NRF2核易位的抑制及其下游级联失活，从而阻碍抗氧化防御。研究结果表明口服亚慢性暴露 OTA 显着促进 DSS 诱导的结肠炎和结肠炎相关的 CRC 发展。这些结果进一步阐明了 RINCK 通过介导 NRF2 降解在结肠炎进展中的潜在作用，并且可以被视为治疗此类疾病的治疗靶点。版权所有 © 2023。由 Elsevier GmbH 出版。

Mycotoxins, such as aflatoxin and ochratoxin A (OTA), are found at measurable levels in many staple foods; the health implications of long-term exposure of such toxins are poorly understood. Increasing evidence has confirmed the important role of OTA in upregulation of oxidative stress- and inflammatory response-induced tissue injury. However, it remains unknown whether ochratoxin A can promote chronic colitis and its associated colon cancer (CRC) development, and potential molecular mechanism. Additionally, RING finger-interacting protein with C kinase (RINCK) is a ubiquitin ligase and mediates immune response. Unfortunately, the potential molecular function of RINCK on regulation of colitis is still largely unknown.This study aims to provide mechanistic evidence that the role of RINCK in colitis and early colorectal cancer progression in response to OTA treatment via targeting nuclear factor erythroid 2-related factor 2 (NRF2).The Cancer Genome Atlas (TCGA) database, GEO database, human subjects with CC phenotype and CC cell lines were used in this work. Pathological links between OTA, RINCK and treatment of CC are revealed through comprehensive means such as biological information analysis, clinical experiments, RNA-seq, and verification experiments.In this study, under oxidative stress in setting of colitis, we first identified RINCK as a key regulatory factor and a novel endogenous suppressor of nuclear factor erythroid 2-related factor 2 (NRF2), and we also confirm that RINCK is a NRF2 partner protein that catalyses its ubiquitination and degradation in intestinal epithelial cells (IECs). Notably, in vivo study, pathological phenotypes triggered by OTA pretreatment, accompanied by post-treatment of dextran sulfate sodium (DSS)-induced colitis was significantly mitigated by IEC-specific deficiency of Rinck, IEC-Rinck(KO) and adenovirus-associated virus (AAV)-triggered suppression of Rinck in rodent model, and lentivirus (LV)-mediated downregulation of Rinck (LV-shRinck) in rabbit model, as determined by decreased endogenous reactive oxygen species (ROS) production, pro-inflammatory cytokines contents, improved body weights, reduced survival rates, restored colon length, assuasive DAI and histological scores. Inversely, transgenic mice by IEC-specific Rinck overexpression, IEC-Rinck(OE) accelerated colitis in acute or chronic colitis rodent models and in vitro experiments. Moreover, we found that OTA pretreatment-promoted azoxymethane (AOM)/DSS-induced colitis-associated early colorectal cancer (CRC) was also dramatically reduced by IEC-Rinck(KO), indicated by the decreased tumor number and corresponding KI-67 levels. Clinical samples analysis revealed that RINCK levels were greatly increased in tumor tissues of patients with CRC phenotypes. In parallel, RINCK deletion remarkably retarded the proliferation of colon cancer and tumor growth in vitro and in vivo, respectively. Mechanistically, in response to onset of colitis, RINCK directly interacts with NRF2 and promotes ubiquitin-proteasome degradation via increasing K48-linkage ubiquitin chain, thus leads in suppression of NRF2 nuclear translocation and its downstream cascade inactivation, which retards antioxidant defense.The findings suggested that oral sub-chronic exposure of OTA significantly facilitates DSS-induced colitis and colitis-associated CRC development. These results further elucidated the potential role of RINCK in colitis progression by mediating NRF2 degradation, and could be considered as a therapeutic target for the treatment of such disease.Copyright © 2023. Published by Elsevier GmbH.