核因子E2相关因子2-类似Ech相关蛋白（NRF2-KEAP1）途径是细胞对氧化应激的主要防御机制。然而，NRF2-KEAP1信号通路在慢性肝病发展中的作用仍不清楚。在肝脏切除手术期间收集了50例非酒精性脂肪性肝炎（NASH）发展的肝细胞癌（HCC）、49例由慢性丙型肝炎（CHc）发展的肝细胞癌（HCC）和48例结直肠癌（CRC）的肝转移病例的肝脏临床标本，包括肿瘤和非肿瘤区域，通过苏木精-伊红、马氏三色染色、NRF2和KEAP1的免疫组织化学分析进行评估，并与临床病理信息进行比较。NASH和CHc的低强度NRF2组与高强度NRF2组之间的肝脏炎症和纤维化情况比较严重（CRC与NASH：炎症：p = 0.003，纤维化：p = 0.014；CRC与CHc：炎症：p = 0.031，纤维化：p = 0.011），这可能表明肝细胞细胞质中的NRF2表达与非肿瘤区域的肝炎和纤维化呈负相关。非肿瘤肝细胞细胞核中NRF2的浓染与肝脏炎症（CRC和NASH; R = 0.451, p < 0.001, CRC和CHc; R = 0.502, p < 0.001）和纤维化（CRC和NASH; R = 0.566, p < 0.001, CRC和CHc; R = 0.548, p < 0.001）呈正相关，并与血小板计数等肝脏储备功能相关的指标如凝血酶原时间（R = -0.206, p = 0.012）呈负相关。然而，KEAP1的表达与NRF2的表达水平和核染色强度无关。NRF2的核转位与慢性肝病肝脏炎症和纤维化的程度相关。这些结果表明NRF2在NASH和CHc等慢性肝病的发展中发挥了保护作用。 ©2023 The Authors. Cancer Medicine由John Wiley & Sons Ltd.发布。

The nuclear factor E2-related factor 2-Kelch-like Ech-associated protein (NRF2-KEAP1) pathway is a major cellular defense mechanism against oxidative stress. However, the role of NRF2-KEAP1 signaling in the development of chronic liver disease remains unclear.Clinical liver specimens from 50 hepatocellular carcinoma (HCC) developed from non-alcoholic steatohepatitis (NASH), 49 HCCs developed from chronic viral hepatitis C (CHc), and 48 liver metastases of colorectal cancer (CRC) from both tumorous and non-tumorous areas were collected during hepatic resection surgery. They were evaluated by immunohistochemical analyses of hematoxylin-eosin, Masson's trichrome, NRF2, and KEAP1, and compared with clinicopathological information.Hepatic inflammation and fibrosis were more severe in the low-intensity NRF2 group than in the high-intensity NRF2 group both between CRC and NASH (Low vs. High: inflammation; p = 0.003, fibrosis; p = 0.014), and between CRC and CHc (Low vs. High: inflammation; p = 0.031, fibrosis; p = 0.011), which could indicate that NRF2 expression in cytosol of hepatocytes was inversely correlated with liver inflammation and fibrosis in non-tumorous areas. The dense staining of NRF2 in the nuclei of non-tumor hepatocytes positively correlated with liver inflammation (CRC and NASH; R = 0.451, p < 0.001, CRC and CHc; R = 0.502, p < 0.001) and fibrosis (CRC and NASH; R = 0.566, p < 0.001, CRC and CHc; R = 0.548, p < 0.001) in both NASH and CHc, and was inversely correlated with hepatic spare ability features such as platelet count (R = -0.253, p = 0.002) and prothrombin time (R = -0.206, p = 0.012). However, KEAP1 expression was not correlated with NRF2 expression levels and nuclear staining intensity.Nuclear translocation of NRF2 was correlated with the magnitude of liver inflammation and fibrosis in chronic liver disease. These results suggest that NRF2 plays a protective role in the development of chronic liver diseases such as NASH and CHc.© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.