摘要
代谢相关脂肪性肝病(metabolic associated fatty liverdisease,MAFLD),曾用名非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD),在世界范围内的全球患病率已经飙升至29.8%,成为最为常见的慢性肝病。截止目前,FDA仅批准了resmetirom一款药物用于治疗伴有中度至晚期肝瘢痕形成(纤维化)的代谢功能障碍相关脂肪性肝炎(MASH)成人患者,针对治疗MAFLD的靶点发现和药物研究仍有巨大缺口。G蛋白偶联受体(G-protein-coupled receptor,GPCR)家族作为人体细胞分布最广泛的膜蛋白家族,参与各项内环境的生理信号调控,被用作多种代谢性疾病的治疗靶点,并已在MAFLD的药物研发中取得了重要进展。本综述对GPCR在治疗MAFLD/MASH方面的研究及药物开发进展进行了简要总结,以GPCR配体种类及偶联G蛋白类型作为标准,分类回顾了与胰高糖素样肽-1受体、趋化因子受体、血管紧张素受体、β肾上腺素受体等已经在MAFLD及相关代谢性疾病中表现出治疗作用或潜力的GPCR的研究进展,及部分相关药物的临床试验结果。并基于研究现状,为GPCR用于MAFLD治疗的可能发展方向提出了靶向糖脂代谢共调节、靶向肝纤维化、加强偏向性激动剂研究的预测,希望为相关研究提供参考。
Metabolic associated fatty liver disease(MAFLD),previously named nonalcoholic fatty liver disease(NAFLD),has surged to a global prevalence of 29.8%,developing the most prevalent chronic liver disease worldwide.To date,the FDA has approved only resmetirom for treating adults with metabolic associated steatohepatitis(MASH)accompanied by moderate to advanced liver fibrosis.These highlight a substantial unmet need for target discovery and therapeutic development in MAFLD management.G protein-coupled receptor(GPCR),the most extensively distributed membrane protein family in humans,regulates diverse physiological signaling pathways and has emerged as a pivotal therapeutic target for metabolic disorders.Significant progress has been achieved in GPCR-targeted drug development for MAFLD.This review systematically summarizes recent advances in GPCRbased research and pharmacological interventions for MAFLD/MASH,categorizing targets by ligand and coupled G-protein subtypes.With emphasis on their therapeutic potential in MAFLD-related metabolic dysregulation and fibrosis,these receptors discussed include the glucagon-like peptide-1 receptor,chemokine receptors,angiotensin receptors,andβ-adrenergic receptors,etc.Clinical trial outcomes of relevant investigational drugs are critically evaluated.Building on current evidence,the authors proposestrategic directions for future GPCR-targeted MAFLD therapies:Targeting on glucose metabolism,anti-liver fibrosis,and the development of biased agonist towards MAFLD.Hoping these reviews could provide references for related researchon MAFLD/MASH.
作者
才俊泽
欧瑜
CAI Junze;OU Yu(School of Life Science and Technology,China Pharmaceutical University,Nanjing 211098,China)
出处
《药物生物技术》
2025年第3期382-389,共8页
Pharmaceutical Biotechnology
