Novo Nordisk Research Center Indianapolis, Inc., United States.
Novo Nordisk Research Center Indianapolis, Inc., United States.
Mol Metab. 2021 Apr;46:101153. doi: 10.1016/j.molmet.2020.101153. Epub 2020 Dec 23.
Non-alcoholic steatohepatitis (NASH) is a spectrum of histological liver pathologies ranging from hepatocyte fat accumulation, hepatocellular ballooning, lobular inflammation, and pericellular fibrosis. Based on early investigations, it was discovered that visceral fat accumulation, hepatic insulin resistance, and atherogenic dyslipidemia are pathological triggers for NASH progression. As these pathogenic features are common with obesity, type 2 diabetes (T2D), and atherosclerosis, therapies that target dysregulated core metabolic pathways may hold promise for treating NASH, particularly as first-line treatments.
In this review, the latest clinical data on nuclear hormone- and peptide hormone-based drug candidates for NASH are reviewed and contextualized, culminating with a discovery research perspective on emerging combinatorial therapeutic approaches that merge nuclear and peptide strategies.
Several drug candidates targeting the metabolic complications of NASH have shown promise in early clinical trials, albeit with unique benefits and challenges, but questions remain regarding their translation to larger and longer clinical trials, as well as their utility in a more diseased patient population. Promising polypharmacological approaches can potentially overcome some of these perceived challenges, as has been suggested in preclinical models, but deeper characterizations are required to fully evaluate these opportunities.
非酒精性脂肪性肝炎（NASH）是一种从肝细胞脂肪堆积、肝细胞气球样变、肝小叶炎症和细胞周围纤维化等一系列组织学肝病理变化的谱。基于早期的研究发现，内脏脂肪堆积、肝胰岛素抵抗和致动脉粥样硬化性血脂异常是 NASH 进展的病理触发因素。由于这些致病特征与肥胖、2 型糖尿病（T2D）和动脉粥样硬化症共有的，因此针对失调的核心代谢途径的治疗方法可能有望治疗 NASH，特别是作为一线治疗方法。
在这篇综述中，回顾和阐述了基于核激素和肽激素的 NASH 候选药物的最新临床数据，最终从发现研究的角度探讨了新兴的联合治疗方法，将核和肽策略相结合。
几种针对 NASH 代谢并发症的候选药物在早期临床试验中显示出有希望的结果，尽管具有独特的益处和挑战，但仍存在一些问题，需要在更大规模和更长时间的临床试验中进行转化，以及在更具疾病特征的患者群体中的应用。有前途的多药物治疗方法可能有潜力克服一些这些被认为的挑战，正如在临床前模型中所表明的，但需要更深入的特征分析来充分评估这些机会。
