Noguchi Masahito, Miyauchi Aya, Masaki Yoshiaki, Sakaki Masashi, Lei Xiao-Feng, Kobayashi-Tanabe Momoko, Miyazaki Akira, Aoki Takeshi, Yoshida Hitoshi, Seio Kohji, Kim-Kaneyama Joo-Ri
Department of Biochemistry, Showa University School of Medicine; Shinagawa-ku, Tokyo, Japan.
Institute for Extracellular Matrix Research, Showa University; Shinagawa-ku, Tokyo, Japan.
JHEP Rep. 2024 Aug 23;6(11):101195. doi: 10.1016/j.jhepr.2024.101195. eCollection 2024 Nov.
BACKGROUND & AIMS: Chronic liver diseases, including metabolic dysfunction-associated steatohepatitis (MASH), pose a significant global health burden. Progressive liver fibrosis can lead to severe outcomes; however, there is a lack of effective therapies targeting advanced fibrosis. Hydrogen peroxide-inducible clone-5 (Hic-5), an adaptor protein in focal adhesion, is critical for promoting liver fibrosis in hepatic stellate cells. This study investigated its clinical applicability by examining hepatic Hic-5 expression in human fibrotic tissues, exploring its association with MASH, and assessing the therapeutic potential of antisense oligonucleotides (ASOs) targeting Hic-5 in a MASH mouse model.
Hepatic Hic-5 expression in human fibrotic tissues underwent pathological image analysis and single-cell RNA sequencing. ASOs targeting Hic-5 were developed and tested using cell models. An MASH mouse model was used to evaluate the effects of anti- ASOs on advanced fibrosis and steatosis.
Hepatic Hic-5 expression increased with the progression of fibrosis, particularly in advanced stages. Single-cell RNA sequencing revealed Hic-5 expression primarily in hepatic stellate cells. In MASH-associated fibrosis, Hic-5 expression correlated with the expression of fibrotic genes. In the MASH mouse model, hepatic Hic-5 expression increased with disease progression. Anti- ASOs effectively suppressed Hic-5 expression and attenuated advanced fibrosis and steatosis , indicating their therapeutic potential.
Hepatic Hic-5 expression is associated with advanced liver fibrosis and MASH. Anti- ASOs are promising therapeutic interventions for MASH accompanied by advanced fibrosis. These findings provide valuable insights into potential clinical treatments for advanced liver fibrosis.
This study investigated the role of Hic-5 in liver fibrosis and steatohepatitis, highlighting its potential as a therapeutic target. We developed an antisense oligonucleotide (ASO) that was particularly transportable to the liver, and targeted Hic-5. Anti- ASO exhibited therapeutic efficacy for liver fibrosis and steatosis , indicating its therapeutic potential for liver fibrosis and steatosis. ASOs have already achieved dramatic therapeutic effects as approved nucleic acid drugs. Thus, anti- ASO is expected to lead the direct generation of seed compounds for the clinical development of drugs for liver fibrosis and steatosis.
慢性肝病，包括代谢功能障碍相关脂肪性肝炎（MASH），构成了重大的全球健康负担。进行性肝纤维化可导致严重后果；然而，针对晚期纤维化缺乏有效的治疗方法。过氧化氢诱导克隆5（Hic-5）是一种粘着斑中的衔接蛋白，对促进肝星状细胞中的肝纤维化至关重要。本研究通过检测人纤维化组织中肝脏Hic-5的表达、探索其与MASH的关联以及评估靶向Hic-5的反义寡核苷酸（ASO）在MASH小鼠模型中的治疗潜力，来研究其临床适用性。
对人纤维化组织中的肝脏Hic-5表达进行病理图像分析和单细胞RNA测序。开发了靶向Hic-5的ASO并使用细胞模型进行测试。使用MASH小鼠模型评估抗ASO对晚期纤维化和脂肪变性的影响。
肝脏Hic-5表达随纤维化进展而增加，尤其是在晚期。单细胞RNA测序显示Hic-5主要在肝星状细胞中表达。在MASH相关纤维化中，Hic-5表达与纤维化基因的表达相关。在MASH小鼠模型中，肝脏Hic-5表达随疾病进展而增加。抗ASO有效抑制Hic-5表达，并减轻晚期纤维化和脂肪变性，表明其治疗潜力。
肝脏Hic-5表达与晚期肝纤维化和MASH相关。抗ASO是伴有晚期纤维化的MASH有前景的治疗干预措施。这些发现为晚期肝纤维化的潜在临床治疗提供了有价值的见解。
本研究调查了Hic-5在肝纤维化和脂肪性肝炎中的作用，突出了其作为治疗靶点的潜力。我们开发了一种特别可转运至肝脏并靶向Hic-5的反义寡核苷酸（ASO）。抗ASO对肝纤维化和脂肪变性表现出治疗效果，表明其对肝纤维化和脂肪变性的治疗潜力。ASO作为已获批的核酸药物已取得显著治疗效果。因此，抗ASO有望直接产生用于肝纤维化和脂肪变性药物临床开发的先导化合物。
