Non-alcoholic steatohepatitis (NASH) - a hepatic manifestation of the metabolic syndrome - is a multifactorial disease with alarming global prevalence. It involves steatosis, inflammation and fibrosis in the liver, thus demanding multiple modes of action for robust therapeutic efficacy. Aiming to fuse complementary validated anti-NASH strategies in a single molecule, we have designed and systematically optimized a scaffold for triple activation of farnesoid X receptor (FXR), peroxisome proliferator-activated receptor (PPAR) α and PPARδ. Pilot profiling of the resulting triple modulator demonstrated target engagement in native cellular settings and in mice, rendering it a suitable tool to probe the triple modulator concept in vivo. In DIO NASH in mice, the triple agonist counteracted hepatic inflammation and reversed hepatic fibrosis highlighting the potential of designed polypharmacology in NASH.

非酒精性脂肪性肝炎 (NASH) - 代谢综合征的一种肝脏表现 - 是一种多因素疾病，全球流行率惊人。它涉及肝脏中的脂肪变性、炎症和纤维化，因此需要多种作用模式才能获得强大的治疗效果。为了在单个分子中融合经过验证的互补抗 NASH 策略，我们设计并系统地优化了一种支架，用于法尼醇 X 受体 (FXR)、过氧化物酶体增殖物激活受体 (PPAR) α 和 PPARδ 的三重激活。对由此产生的三重调制器的试验分析表明，目标参与了原生细胞环境和小鼠，使其成为探索体内三重调制器概念的合适工具。在小鼠的 DIO NASH 中，