小柯机器人

美国基因泰克公司Ning Ding团队近期取得重要工作进展，他们研究发现WISP1抗体抑制MRTF信号传导可防止已形成的肝纤维化的进展。相关工作2022年8月19日在线发表于《细胞—代谢》杂志上。

研究人员确定了一条涉及WNT1诱导型信号通路蛋白1（WISP1）和心肌蛋白相关转录因子（MRTF）的通路，作为驱动肝纤维化进展的核心机制，通过整合素依赖的转录重新规划肌纤维细胞骨架和运动。在小鼠中，WISP1缺乏可防止纤维化进展，但不能抑制纤维化发生。

此外，阻断WISP1的新型抗体的治疗性给药阻止了NASH模型中现有肝纤维化的进展。这些发现表明，WISP1-MRTF轴是肝脏纤维化进展的一个关键决定因素，并支持通过基于抗体的疗法来靶向这一途径，以治疗NASH纤维化。

据介绍，纤维化是与非酒精性脂肪性肝炎（NASH）驱动的慢性肝病患者发病率和死亡率相关的主要危险因素。尽管已经做出了许多努力来确定介导肝纤维化起始的相关因素，但对纤维化病变的分子基础仍然知之甚少，并且缺乏阻止肝纤维化进程的治疗方法。

附：英文原文

Title: A WISP1 antibody inhibits MRTF signaling to prevent the progression of established liver fibrosis

Author: Ying Xi, Ryan LaCanna, Hsiao-Yen Ma, Elsa-Noah N’Diaye, Sarah Gierke, Patrick Caplazi, Meredith Sagolla, Zhiyu Huang, Laura Lucio, Alexander Arlantico, Surinder Jeet, Hans Brightbill, Claire Emson, Aaron Wong, Katrina B. Morshead, Daryle J. DePianto, Merone Roose-Girma, Charles Yu, Lucinda Tam, Guiquan Jia, Thirumalai R. Ramalingam, Scot Marsters, Avi Ashkenazi, Si Hyun Kim, Ryan Kelly, Shuang Wu, Paul J. Wolters, Ariel E. Feldstein, Jason A. Vander Heiden, Ning Ding

Issue&Volume: 2022-08-19

Abstract: Fibrosis is the major risk factor associated with morbidity and mortality in patients with non-alcoholic steatohepatitis (NASH)-driven chronic liver disease. Although numerous efforts have been made to identify the mediators of the initiation of liver fibrosis, the molecular underpinnings of fibrosis progression remain poorly understood, and therapies to arrest liver fibrosis progression are elusive. Here, we identify a pathway involving WNT1-inducible signaling pathway protein 1 (WISP1) and myocardin-related transcription factor (MRTF) as a central mechanism driving liver fibrosis progression through the integrin-dependent transcriptional reprogramming of myofibroblast cytoskeleton and motility. In mice, WISP1 deficiency protects against fibrosis progression, but not fibrosis onset. Moreover, the therapeutic administration of a novel antibody blocking WISP1 halted the progression of existing liver fibrosis in NASH models. These findings implicate the WISP1-MRTF axis as a crucial determinant of liver fibrosis progression and support targeting this pathway by antibody-based therapy for the treatment of NASH fibrosis.

DOI: 10.1016/j.cmet.2022.07.009

Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
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