Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
J Intern Med. 2022 Jan;291(1):11-31. doi: 10.1111/joim.13380. Epub 2021 Sep 26.
Non-alcoholic fatty liver disease is comprised of either simple steatosis (non-alcoholic fatty liver) or a more advanced inflammatory and fibrogenic stage (non-alcoholic steatohepatitis [NASH]). NASH affects a growing proportion of the global adult and pediatric population, leading to rising rates of liver fibrosis and hepatocellular carcinoma. NASH is a multifactorial disease that is part of a systemic metabolic disorder. Here, we provide an overview of the metabolic underpinnings of NASH pathogenesis and established drivers of inflammation and fibrosis. Clarification of underlying fibrogenic and inflammatory mechanisms will advance the development of novel treatment strategies as there are no approved therapies at present. We discuss emerging experimental approaches and potential novel investigational strategies derived from animal models including the inflammasome, epigenetic reprogramming, Hippo signaling, Notch signaling, engineered T cells to remove fibrogenic HSCs, and HSC-specific targeting therapies. Recently completed and ongoing clinical trials and antifibrotics are discussed, illuminating the growing expectation that one or more therapies will yield clinical benefit in NASH in the coming years.
非酒精性脂肪性肝病包括单纯性脂肪变性（非酒精性脂肪肝）或更严重的炎症和纤维化阶段（非酒精性脂肪性肝炎[NASH]）。NASH 影响着越来越多的全球成年和儿科人群，导致肝纤维化和肝细胞癌的发病率上升。NASH 是一种多因素疾病，是全身性代谢紊乱的一部分。在这里，我们概述了 NASH 发病机制的代谢基础以及炎症和纤维化的既定驱动因素。阐明潜在的纤维化和炎症机制将促进新的治疗策略的发展，因为目前尚无批准的治疗方法。我们讨论了新兴的实验方法和潜在的新的研究策略，这些策略来自于动物模型，包括炎症小体、表观遗传重编程、 Hippo 信号、Notch 信号、工程化 T 细胞去除成纤维性 HSCs 以及 HSC 特异性靶向治疗。我们还讨论了最近完成和正在进行的临床试验和抗纤维化药物，这表明人们越来越期望在未来几年内，一种或多种疗法将对 NASH 患者带来临床获益。
