Jara Maximilian, Norlin Jenny, Kjær Mette Skalshøi, Almholt Kasper, Bendtsen Kristian M, Bugianesi Elisabetta, Cusi Kenneth, Galsgaard Elisabeth D, Geybels Milan, Gluud Lise L, Harder Lea M, Loomba Rohit, Mazzoni Gianluca, Newsome Philip N, Nitze Louise M, Palle Mads S, Ratziu Vlad, Sejling Anne-Sophie, Wong Vincent W-S, Anstee Quentin M, Knudsen Lotte B
Novo Nordisk, Clinical Development, Søborg, Denmark.
Novo Nordisk, Research & Early Development, Måløv, Denmark.
Nat Med. 2025 Jul 21. doi: 10.1038/s41591-025-03799-0.
Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease strongly associated with cardiometabolic risk factors. Semaglutide, a glucagon-like peptide-1 receptor agonist, improves liver histology in MASH, but the underlying signals and pathways driving semaglutide-induced MASH resolution are not well understood. Here we show that, in two preclinical MASH models, semaglutide improved histological markers of fibrosis and inflammation and reduced hepatic expression of fibrosis-related and inflammation-related gene pathways. Aptamer-based proteomic analyses of serum samples from patients with MASH in a clinical trial identified 72 proteins significantly associated with MASH resolution and semaglutide treatment, with most related to metabolism and several implicated in fibrosis and inflammation. An independent real-world cohort verified the pathophysiological relevance of this signature, showing that the same 72 proteins are differentially expressed in patients with MASH relative to healthy individuals. Taken together, these data suggest that semaglutide may revert the circulating proteome associated with MASH to the proteomic pattern observed in healthy individuals.
代谢功能障碍相关脂肪性肝炎（MASH）是一种与心脏代谢危险因素密切相关的慢性肝病。司美格鲁肽是一种胰高血糖素样肽-1受体激动剂，可改善MASH的肝脏组织学，但驱动司美格鲁肽诱导MASH缓解的潜在信号和途径尚不清楚。在此我们表明，在两种临床前MASH模型中，司美格鲁肽改善了纤维化和炎症的组织学标志物，并降低了纤维化相关和炎症相关基因通路的肝脏表达。在一项临床试验中，基于适体的蛋白质组学分析对MASH患者的血清样本进行分析，确定了72种与MASH缓解和司美格鲁肽治疗显著相关的蛋白质，其中大多数与代谢相关，有几种与纤维化和炎症有关。一个独立的真实世界队列验证了这一特征的病理生理学相关性，表明与健康个体相比，这72种蛋白质在MASH患者中差异表达。综上所述，这些数据表明司美格鲁肽可能使与MASH相关的循环蛋白质组恢复到在健康个体中观察到的蛋白质组模式。
