Xu Xiaohui, Feng Jinmei, Wang Xin, Zeng Xin, Luo Ying, He Xinyu, Yang Meihua, Lv Tiewei, Feng Zijuan, Bao Liming, Zhao Li, Huang Daochao, Huang Yi
Institute of Pediatrics, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China.
Department of Cardiology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Key Cardiovascular Specialty, Laboratory of Children's Important Organ Development and Diseases of Chongqing Municipal Health Commission, Chongqing, China.
J Clin Transl Hepatol. 2024 Jun 28;12(6):539-550. doi: 10.14218/JCTH.2023.00562. Epub 2024 May 28.
Hepatic fibrosis (HF) is a critical step in the progression of hepatocellular carcinoma (HCC). Gene associated with retinoid-IFN-induced mortality 19 (GRIM19), an essential component of mitochondrial respiratory chain complex I, is frequently attenuated in various human cancers, including HCC. Here, we aimed to investigate the potential relationship and underlying mechanism between GRIM19 loss and HF pathogenesis.
GRIM19 expression was evaluated in normal liver tissues, hepatitis, hepatic cirrhosis, and HCC using human liver disease spectrum tissue microarrays. We studied hepatocyte-specific knockout mice and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 (Cas9) lentivirus-mediated gene-editing in murine hepatocyte AML12 cells and . We performed flow cytometry, immunofluorescence, immunohistochemistry, western blotting, and pharmacological intervention to uncover the potential mechanisms underlying GRIM19 loss-induced HF.
Mitochondrial GRIM19 was progressively downregulated in chronic liver disease tissues, including hepatitis, cirrhosis, and HCC tissues. Hepatocyte-specific heterozygous deletion induced spontaneous hepatitis and subsequent liver fibrogenesis in mice. In addition, GRIM19 loss caused chronic liver injury through reactive oxygen species (ROS)-mediated oxidative stress, resulting in aberrant NF-кB activation via an IKK/IкB partner in hepatocytes. Furthermore, GRIM19 loss activated NLRP3-mediated IL33 signaling via the ROS/NF-кB pathway in hepatocytes. Intraperitoneal administration of the NLRP3 inhibitor MCC950 dramatically alleviated GRIM19 loss-driven HF .
The mitochondrial GRIM19 loss facilitates liver fibrosis through NLRP3/IL33 activation via ROS/NF-кB signaling, providing potential therapeutic approaches for earlier HF prevention.
肝纤维化（HF）是肝细胞癌（HCC）进展中的关键步骤。视黄酸-干扰素诱导死亡率相关基因19（GRIM19）是线粒体呼吸链复合体I的重要组成部分，在包括HCC在内的多种人类癌症中经常减弱。在此，我们旨在研究GRIM19缺失与HF发病机制之间的潜在关系及潜在机制。
使用人类肝病谱组织芯片评估正常肝组织、肝炎、肝硬化和HCC中GRIM19的表达。我们研究了肝细胞特异性敲除小鼠，并在小鼠肝细胞AML12细胞中进行了成簇规律间隔短回文重复序列（CRISPR）/CRISPR相关蛋白9（Cas9）慢病毒介导的基因编辑。我们进行了流式细胞术、免疫荧光、免疫组织化学、蛋白质印迹和药理学干预，以揭示GRIM19缺失诱导HF的潜在机制。
线粒体GRIM19在慢性肝病组织（包括肝炎、肝硬化和HCC组织）中逐渐下调。肝细胞特异性杂合缺失诱导小鼠自发性肝炎及随后的肝纤维化。此外，GRIM19缺失通过活性氧（ROS）介导的氧化应激导致慢性肝损伤，通过肝细胞中的IKK/IκB伴侣导致异常的NF-κB激活。此外，GRIM19缺失通过ROS/NF-κB途径在肝细胞中激活NLRP3介导的IL33信号传导。腹腔注射NLRP3抑制剂MCC950可显著减轻GRIM19缺失驱动的HF。
线粒体GRIM19缺失通过ROS/NF-κB信号传导激活NLRP3/IL33促进肝纤维化，为早期HF预防提供了潜在的治疗方法。
