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微RNA在代谢相关脂肪性肝病向肝细胞癌进展中的调控作用
DOI: 10.12449/JCH260425
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作者贡献声明：颉佳丽负责设计论文框架，起草论文，绘制图表，论文写作；刘要男负责论文修改；赵睿负责拟定写作思路，指导撰写文章并最后定稿。
The regulatory role of microRNA in the progression from metabolic dysfunction-associated fatty liver disease to hepatocellular carcinoma
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摘要: 代谢相关脂肪性肝病（MAFLD）是全球慢性肝病的主要病因，最终可导致肝细胞癌的发生。本文概述了MAFLD的定义演变与流行病学负担，以及微RNA（miRNA）的生物合成与功能；详细综述了不同种类的miRNA通过调节脂质代谢、炎症与肝纤维化、氧化应激、内质网应激以及糖酵解等过程，在MAFLD进展中发挥重要调控作用，同时评估了miRNA作为诊断生物标志物与治疗靶点的应用前景。最后指出，尽管现有研究已揭示miRNA在MAFLD进展中的重要作用，但其临床转化仍面临诸多挑战，未来需开展更大规模研究以明确miRNA在MAFLD诊断与治疗中的实际价值，从而为精准医疗开辟新的路径。Abstract: Metabolic dysfunction-associated fatty liver disease （MAFLD） is the main cause of chronic liver disease around the world and can eventually lead to hepatocellular carcinoma. This article describes the evolution of the definition of MAFLD， the epidemiological burden of MAFLD， and the biosynthesis and biological functions of microRNA （miRNA）， as well as the important role of various types of miRNA in the progression of MAFLD by regulating the processes such as lipid metabolism， inflammation and liver fibrosis， oxidative stress， endoplasmic reticulum stress， and glycolysis. This article also evaluates the application prospect of miRNA as diagnostic biomarkers and therapeutic targets. It is pointed out that although existing studies have shown that miRNA plays an important role in the progression of MAFLD， there are still challenges in clinical translation， and large-scale studies should be conducted in the future to clarify the practical value of miRNA in MAFLD diagnosis and treatment， thereby providing new ways for precision medicine.
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注： Pol Ⅱ，RNA聚合酶Ⅱ；Drosha-DGCR8，微处理器复合物；pri-miRNA，初级miRNA；pre-miRNA，前体miRNA；Ran-GTP，鸟苷三磷酸Ran蛋白；Exportin-5，输出蛋白-5；TRBP，反式激活应答RNA结合蛋白；Dicer，Dicer酶；Ago，Argonaute蛋白；RISC，RNA诱导的沉默复合物。
图 1 miRNA的生物合成过程
Figure 1. Schematic diagram of miRNA biosynthesis
表 1 MAFLD/MASH中与脂代谢相关的miRNA的表达变化、分子机制及治疗潜力
Table 1. Summary of studies on expression changes，molecular mechanisms and therapeutic potential of miRNA related to lipid metabolism in MAFLD/MASH
miRNA 表达变化 核心靶点/通路 功能机制 治疗潜力 文献 miRNA-34a 上调 SIRT1、 PPARα 抑制脂肪酸氧化，促进炎症
反应拮抗剂则改善脂肪
变性［25］ miRNA-33b 上调 SREBP-1 促进胆固醇合成 抗miRNA-33b延缓
MASH进展［27］ miRNA-30b-5p 下调 SREBP-1 抑制脂质合成基因表达 模拟物减少肝细胞脂
滴积累［28］ miRNA-103-3p 上调 ACOX1 抑制过氧化物酶体β氧化 拮抗剂改善氧化应激 ［30］ miRNA-124-3p 上调（高脂饮食小鼠） Pref-1 负调控Pref-1，促进脂质
积累靶向miRNA-124-3p/Pref-1轴或可改善肝
脂肪变性［32］ miRNA-130b-5p 上调 IGFBP2 抑制AKT通路，促进胰岛素
抵抗拮抗剂改善胰岛素敏
感性［34］ miRNA-379/miRNA-544簇 上调（高脂饮食小鼠） IGF1R/DLK1信号 簇缺失改善代谢紊乱；
miRNA-379直接抑制IGF1R
和DLK1，促进脂质沉积抑制该簇或可增强胰
岛素样生长因子1信
号，减轻MAFLD［35］ 注：SIRT1，去乙酰化酶1；PPARα，过氧化物酶体增殖物激活受体α；SREBP-1，固醇调节元件结合蛋白1；MASH，代谢相关脂肪性肝炎；ACOX1，酰基辅酶A氧化酶1；Pref-1，前脂肪细胞因子1；IGFBP2，胰岛素样生长因子结合蛋白2；AKT，蛋白激酶B；IGF1R胰岛素样生长因子1受体；DLK1，δ样同源物1；MAFLD，代谢相关脂肪性肝病。
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表 2 MAFLD/MASH中与应激和代谢相关的miRNA的表达变化、分子机制及治疗潜力
Table 2. Summary of studies on expression changes， molecular mechanisms and therapeutic potential of stress and metabolism-related miRNA in MAFLD/MASH
miRNA 表达变化 核心靶点/通路 功能机制 治疗潜力 文献 miRNA-26a 下调（MAFLD） 内质网应激/eIF2α
通路内质网应激诱导miRNA-26a上调，
反馈性缓解内质网应激和脂质积
累；缺失加重肝损伤恢复miRNA-26a水平或可
减轻内质网应激和脂肪
变性［36］ miRNA-137-3p 下调（MAFLD） PDE4D/AMPKα
通路激活AMPKα减轻氧化应激和炎症
反应；而拮抗剂则加重高脂肪饮食
诱发的肝损伤miRNA-137-3p类似物或为
抗氧化应激治疗策略［37］ miRNA-122-5p 下调（MASH） PKM2/糖酵解途径 下调导致Kupffer细胞Warburg效应
增强，促进炎症反应和癌前病变补充miRNA-122-5p或抑制
PKM2可改善MASH进程［38］ miRNA-22 下调（HCC/MASH） TSP1/代谢相关基因 缺失促进肿瘤发生，影响线粒体功
能和代谢重编程；多重调控致癌因
子和分化相关基因miRNA-22替代疗法或可延
缓MASH相关HCC进展［39］ 注：MAFLD，代谢相关脂肪性肝病；MASH，代谢相关脂肪性肝炎；eIF2α，真核翻译起始因子2α亚基；PDE4D，磷酸二酯酶4D；AMPKα，腺苷-磷酸活化蛋白激酶α亚基；PKM2，丙酮酸激酶肌肉同工酶2；HCC，肝细胞癌；TSP1，血小板反应蛋白1。
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