Department of Discovery Immunology, Genentech, South San Francisco, CA, USA.
Department of Pathology, Genentech, South San Francisco, CA, USA.
Cell Metab. 2022 Sep 6;34(9):1377-1393.e8. doi: 10.1016/j.cmet.2022.07.009. Epub 2022 Aug 19.
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.
纤维化是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的主要相关风险因素。尽管已经做出了许多努力来确定肝纤维化起始的介质，但纤维化进展的分子基础仍知之甚少，并且难以找到阻止肝纤维化进展的疗法。在这里，我们确定了一条涉及 WNT1 诱导信号通路蛋白 1（WISP1）和肌球蛋白相关转录因子（MRTF）的途径，作为通过整合素依赖性肌成纤维细胞细胞骨架和运动的转录重编程驱动肝纤维化进展的核心机制。在小鼠中，WISP1 缺乏可预防纤维化进展，但不能预防纤维化发生。此外，新型抗 WISP1 抗体的治疗性给药可阻止 NASH 模型中现有肝纤维化的进展。这些发现表明 WISP1-MRTF 轴是肝纤维化进展的关键决定因素，并支持通过基于抗体的治疗针对该途径治疗 NASH 纤维化。
