Liver homeostasis is strongly influenced by the circadian clock, an evolutionarily conserved mechanism synchronising physiology and behaviour across a 24-hour cycle. Disruption of the clock has been heavily implicated in the pathogenesis of metabolic dysfunction including non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). Furthermore, many of the current NASH drug candidates specifically target pathways known to be under circadian control including fatty acid synthesis and signalling via the farnesoid X receptor, fibroblast growth factor 19 and 21, peroxisome proliferator-activated receptor α and γ, glucagon-like peptide 1, and the thyroid hormone receptor. Despite this, there has been little consideration of the application of chronopharmacology in NASH, a strategy whereby the timing of drug delivery is informed by biological rhythms in order to maximise efficacy and tolerability. Chronopharmacology has been shown to have significant clinical benefits in a variety of settings including cardiovascular disease and cancer therapy. The rationale for its application in NASH is therefore compelling. However, no clinical trials in NASH have specifically explored the impact of drug timing on disease progression and patient outcomes. This may contribute to the wide variability in reported outcomes of NASH trials and partly explain why even late-phase trials have stalled because of a lack of efficacy or safety concerns. In this opinion piece, we describe the potential for chronopharmacology in NASH, discuss how the major NASH drug candidates are influenced by circadian biology, and encourage greater consideration of the timing of drug administration in the design of future clinical trials.

肝脏稳态受生物钟的强烈影响，生物钟是一种在 24 小时周期内同步生理和行为的进化保守机制。生物钟的破坏与代谢功能障碍的发病机制密切相关，包括非酒精性脂肪肝 (NAFL) 和非酒精性脂肪性肝炎 (NASH)。此外，目前许多 NASH 候选药物专门针对已知受昼夜节律控制的途径，包括脂肪酸合成和通过法尼醇 X 受体、成纤维细胞生长因子 19 和 21、过氧化物酶体增殖物激活受体 α 和 γ、胰高血糖素样肽的信号传导1、与甲状腺激素受体有关。尽管如此，很少考虑时间药理学在 NASH 中的应用，一种策略，通过生物节律来告知药物输送的时间，以最大限度地提高疗效和耐受性。时间药理学已被证明在包括心血管疾病和癌症治疗在内的各种环境中具有显着的临床益处。因此，其在 NASH 中应用的理由是令人信服的。然而，没有 NASH 的临床试验专门探讨药物时机对疾病进展和患者预后的影响。这可能导致 NASH 试验报告结果的广泛变异性，并部分解释了为什么即使是后期试验也由于缺乏疗效或安全性问题而停滞不前。在这篇评论文章中，我们描述了 NASH 中时间药理学的潜力，讨论了主要的 NASH 候选药物如何受到昼夜节律生物学的影响，