药学学报

Type	Program	Indication	Phase
Monoclonal antibody	AMG529	Hypercholesterolemia	Phase Ⅰ completed
Monoclonal antibody	4B9	Hypercholesterolemia	Preclinical
Bispecific antibody	SZN-043	Alcoholic hepatitis, cirrhosis	Phase Ⅰ
Antibody-immunomodulator conjugate	SBT8230	Chronic hepatitis B, hepatocellular carcinoma	Preclinical

Type

Program

Indication

Phase

Monoclonal antibody

AMG529

Hypercholesterolemia

Phase Ⅰ completed

Monoclonal antibody

4B9

Hypercholesterolemia

Preclinical

Bispecific antibody

SZN-043

Alcoholic hepatitis, cirrhosis

Phase Ⅰ

Antibody-immunomodulator conjugate

SBT8230

Chronic hepatitis B, hepatocellular carcinoma

Preclinical

Type	Program	Indication	Phase
Monoclonal antibody	AMG529	Hypercholesterolemia	Phase Ⅰ completed
Monoclonal antibody	4B9	Hypercholesterolemia	Preclinical
Bispecific antibody	SZN-043	Alcoholic hepatitis, cirrhosis	Phase Ⅰ
Antibody-immunomodulator conjugate	SBT8230	Chronic hepatitis B, hepatocellular carcinoma	Preclinical

Type

Program

Indication

Phase

Monoclonal antibody

AMG529

Hypercholesterolemia

Phase Ⅰ completed

Monoclonal antibody

4B9

Hypercholesterolemia

Preclinical

Bispecific antibody

SZN-043

Alcoholic hepatitis, cirrhosis

Phase Ⅰ

Antibody-immunomodulator conjugate

SBT8230

Chronic hepatitis B, hepatocellular carcinoma

Preclinical

Type	Program	Delivery system	Indication	FDA approval	Company
siRNA	RIVFLOZA^® (nedosiran)	GalXC^TM-RNAi platform	Primary hyperoxaluria type 1	2023	Novo Nordisk
siRNA	AMVUTTRA^® (vutrisiran)	GalNAc-siRNA	hATTR amyloidosis with polyneuropathy	2022	Alnylam
siRNA	LEQVIO^® (inclisiran)	GalNAc-siRNA	Hypercholesterolemia	2021	Alnylam
siRNA	OXLUMO^® (lumasiran)	GalNAc-siRNA	Primary hyperoxaluria type 1	2020	Novartis
siRNA	GIVLAARI^® (givosiran)	GalNAc-siRNA	Acute hepatic porphyria	2019	Alnylam
ASO	Tryngolza^TM (olezarsen)	GalNAc-ASO	Familial chylomicronemia syndrome	2024	Ionis

Type

Program

Delivery system

Indication

FDA approval

Company

siRNA

RIVFLOZA^® (nedosiran)

GalXC^TM-RNAi platform

Primary hyperoxaluria type 1

2023

Novo Nordisk

siRNA

AMVUTTRA^® (vutrisiran)

GalNAc-siRNA

hATTR amyloidosis with polyneuropathy

2022

Alnylam

siRNA

LEQVIO^® (inclisiran)

GalNAc-siRNA

Hypercholesterolemia

2021

Alnylam

siRNA

OXLUMO^® (lumasiran)

GalNAc-siRNA

Primary hyperoxaluria type 1

2020

Novartis

siRNA

GIVLAARI^® (givosiran)

GalNAc-siRNA

Acute hepatic porphyria

2019

Alnylam

ASO

Tryngolza^TM (olezarsen)

GalNAc-ASO

Familial chylomicronemia syndrome

2024

Ionis

Type	Program	Delivery system	Indication	FDA approval	Company
siRNA	RIVFLOZA^® (nedosiran)	GalXC^TM-RNAi platform	Primary hyperoxaluria type 1	2023	Novo Nordisk
siRNA	AMVUTTRA^® (vutrisiran)	GalNAc-siRNA	hATTR amyloidosis with polyneuropathy	2022	Alnylam
siRNA	LEQVIO^® (inclisiran)	GalNAc-siRNA	Hypercholesterolemia	2021	Alnylam
siRNA	OXLUMO^® (lumasiran)	GalNAc-siRNA	Primary hyperoxaluria type 1	2020	Novartis
siRNA	GIVLAARI^® (givosiran)	GalNAc-siRNA	Acute hepatic porphyria	2019	Alnylam
ASO	Tryngolza^TM (olezarsen)	GalNAc-ASO	Familial chylomicronemia syndrome	2024	Ionis

Type

Program

Delivery system

Indication

FDA approval

Company

siRNA

RIVFLOZA^® (nedosiran)

GalXC^TM-RNAi platform

Primary hyperoxaluria type 1

2023

Novo Nordisk

siRNA

AMVUTTRA^® (vutrisiran)

GalNAc-siRNA

hATTR amyloidosis with polyneuropathy

2022

Alnylam

siRNA

LEQVIO^® (inclisiran)

GalNAc-siRNA

Hypercholesterolemia

2021

Alnylam

siRNA

OXLUMO^® (lumasiran)

GalNAc-siRNA

Primary hyperoxaluria type 1

2020

Novartis

siRNA

GIVLAARI^® (givosiran)

GalNAc-siRNA

Acute hepatic porphyria

2019

Alnylam

ASO

Tryngolza^TM (olezarsen)

GalNAc-ASO

Familial chylomicronemia syndrome

2024

Ionis

肝脏去唾液酸糖蛋白受体1在代谢疾病中的作用及药物研究进展

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吴敏 , 冯存玉 , 郝思铭 , 雷蕾 ^* , 环奕 ^*

药学学报 | 综述 2026,61(1): 75-83

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药学学报 |综述 2026 , 61 (1) : 75 -83

肝脏去唾液酸糖蛋白受体1在代谢疾病中的作用及药物研究进展

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吴敏, 冯存玉, 郝思铭, 雷蕾^*, 环奕^*

作者信息

中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050

通讯作者:

雷蕾, Tel: 86-10-63165194, E-mail: dlei228@imm.ac.cn

环奕, Tel: 86-10-63165194, E-mail: huany@imm.ac.cn

作者简介:

作者贡献:

吴敏负责组织文章的框架、文章的撰写及修改; 环奕负责文章的思路指导和审阅; 冯存玉、郝思铭和雷蕾对稿件进行了完善。

The role of liver asialoglycoprotein receptor 1 in metabolic diseases and the research progress of drugs

Min WU, Cun-yu FENG, Si-ming HAO, Lei LEI^*, Yi HUAN^*

Affiliations

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

出版时间: 2026-01-12 doi: 10.16438/j.0513-4870.2025-0731

文章导航

摘要

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在代谢性疾病的防治领域, 肝脏作为核心代谢器官, 其功能状态对疾病的发展和治疗策略选择具有重要影响。近年来, 随着对肝脏受体分子的深入研究, 去唾液酸糖蛋白受体1 (asialoglycoprotein receptor 1, ASGR1)因其在糖蛋白识别、脂质代谢调节及免疫调控等方面的作用, 逐渐受到关注。尽管已有研究提示ASGR1功能紊乱与多种代谢性疾病密切相关, 但将其直接作为治疗靶点尚存在较大争议, 需要进一步研究其作为肝脏靶点的可行性和疗效。另一方面, 基于ASGR1介导的肝靶向递送系统已在多个药物开发中展现出临床应用潜力。本文系统梳理了ASGR1的生理功能及其在代谢疾病中的研究进展, 重点讨论其分子调控机制与药物应用前景, 以期为肝脏相关代谢疾病的诊疗策略提供参考。

关键词

去唾液酸糖蛋白受体1 / 肝脏 / 胆固醇 / 代谢疾病

Abstract

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In the field of prevention and treatment of metabolic diseases, liver is the core metabolic organ, and its functional status has an important impact on the development of diseases and the selection of treatment strategies. In recent years, with the in-depth study of liver receptor molecules, asialoglycoprotein receptor 1 (ASGR1) has gradually attracted attention because of its role in glycoprotein recognition, lipid metabolism regulation, and immune regulation. Although studies have suggested that ASGR1 dysfunction is closely related to a variety of metabolic diseases, it is still controversial to directly use ASGR1 as a therapeutic target, and further studies are needed to explore the feasibility and efficacy of ASGR1 as a liver target. On the other hand, ASGR1-mediated liver-targeted delivery systems have shown clinical application potential in multiple drug development. This article systematically reviews the physiological functions of ASGR1 and its research progress in metabolic diseases, focusing on its molecular regulatory mechanisms and drug application prospects, in order to provide reference for the diagnosis and treatment strategies of liver-related metabolic diseases.

Key words

asialoglycoprotein receptor 1 / liver / cholesterol / lipid metabolism

引用本文

吴敏, 冯存玉, 郝思铭, 雷蕾, 环奕. 肝脏去唾液酸糖蛋白受体1在代谢疾病中的作用及药物研究进展. 药学学报, 2026 , 61 (1) : 75 -83 . DOI: 10.16438/j.0513-4870.2025-0731

Min WU, Cun-yu FENG, Si-ming HAO, Lei LEI, Yi HUAN. The role of liver asialoglycoprotein receptor 1 in metabolic diseases and the research progress of drugs[J]. Acta Pharmaceutica Sinica, 2026 , 61 (1) : 75 -83 . DOI: 10.16438/j.0513-4870.2025-0731

正文

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代谢性疾病是一类因体内糖、脂肪、蛋白质、嘌呤、水-电解质等代谢过程紊乱或代谢产物异常积聚所导致的病理状态^[1], 其病理机制涉及能量代谢调控异常、慢性炎症反应和器官间交互作用失调等多个层面^[2]。这类疾病涵盖高血压、2型糖尿病、血脂异常、肥胖症及代谢相关性脂肪性肝病等多个慢性疾病^[3-6], 各疾病间不仅共享遗传易感性、营养过剩和体力活动不足等危险因素, 更通过复杂的代谢-炎症网络产生协同效应^[7-12]。

去唾液酸糖蛋白受体1 (asialoglycoprotein receptor 1, ASGR1)是肝细胞表面特异性表达的C型凝集素受体(C-type lectins receptors, CLRs)^[13], 与去唾液酸糖蛋白受体2 (asialoglycoprotein receptor 2, ASGR2)共同构成去唾液酸糖蛋白受体(asialoglycoprotein receptor, ASGPR)^[14-16], 可特异性结合含半乳糖(galactose, Gal)或N-乙酰半乳糖胺(N-acetylgalactosamine, GalNAc)的糖蛋白, 介导配体内吞及溶酶体降解^[17]。基于此特性, ASGR1在代谢性疾病中的作用机制备受关注。本综述将总结ASGR1的生物学功能及在代谢性疾病中的作用机制, 并调研其靶向治疗的临床研究, 展望其在以上疾病中的应用前景。

1　ASGR1的发现

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ASGR1的发现可以追溯到20世纪60年代, Morell等^[18]和Ashwell等^[19]在研究哺乳动物血浆铜蓝蛋白的过程中, 意外发现了一种可以特异性结合去唾液酸糖蛋白的受体, 不仅为糖蛋白的代谢研究开辟了新的道路, 也为后续的脂质代谢研究奠定了基础。由于这一重要发现, 该受体被命名为“Ashwell-Morell受体”, 以纪念两位科学家的贡献。

2　ASGR1结构特征

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ASGR1分为3个主要功能结构域: 胞质结构域、跨膜结构域、胞外结构域^{[20, 21]} (图1)。胞质结构域位于细胞内侧, 含有40个氨基酸残基, 参与ASGR1的细胞内信号传导和与其他蛋白的相互作用。跨膜结构域由约20个氨基酸构成, 负责将ASGR1锚定于肝细胞膜上。胞外区域则由茎区和碳水化合物识别结构域(carbohydrate recognition domain, CRD)组成。茎区含约80个氨基酸残基, 连接跨膜结构域与CRD, 并为CRD提供必要的空间结构支持, 增强其稳定性。CRD是ASGR1最关键的功能区域, 约含140个氨基酸残基, 专职识别和结合特定的去唾液酸糖蛋白配体。该结构域属于C型凝集素超家族, 具有3个高度保守的分子内二硫键, 这些二硫键对于维持CRD的三维构象和识别功能至关重要^[22]。

功能性的ASGPR通常由ASGR1和其同源亚基ASGR2组成异源寡聚体, 二者通过茎段形成稳定的卷曲螺旋结构完成寡聚化^[16], 典型形式为2∶2异源四聚体^[23], 该结构显著增强了ASGPR对配体的亲和力和特异性, 是其功能和稳定性的基础。尽管ASGPR的完整功能通常需要ASGR1与ASGR2协同构建, 但已有研究表明, ASGR1为该复合物中介导配体识别和内吞作用的主要功能亚基, 在ASGR2缺失的条件下, ASGR1仍可维持部分功能^[24]。因此, 本文后续主要聚焦于ASGR1的生物学作用及其在代谢性疾病发生发展中的潜在作用与靶向研究进展。

3　ASGR1生物学功能

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ASGR1最核心的生物学功能是介导去唾液酸糖蛋白的特异性识别与清除, 这一过程构成其在代谢调控、疾病防御及靶向治疗中的基础机制。ASGR1的胞外CRD结构域具有高度糖链特异性, 能够精准识别血液循环中去唾液酸化糖蛋白上暴露的Gal和GalNAc残基, 尤其是三天线或四天线型N-连接糖链的末端结构^{[25, 26]}。与配体结合后, ASGR1通过受体介导的内吞作用将糖蛋白内吞至肝细胞内, 并经内体-溶酶体通路完成降解^[27], 最终代谢为可再利用的小分子营养成分(图1)。该功能对于维持血浆糖蛋白稳态至关重要, 可有效清除老化或异常糖基化蛋白, 避免其在体内蓄积引发免疫或代谢紊乱^[25]。同时, ASGR1对特定糖结构的高度识别性也为其在肝脏靶向递药中提供了理论基础^[28], 后续多种代谢疾病相关功能和治疗策略均建立在这一机制之上。

4　ASGR1与代谢性疾病

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4.1　ASGR1与高血脂

脂质是参与生物能量代谢的重要化学物质^[29], 脂质代谢异常通常会导致内分泌激素紊乱, 并进一步发展为肥胖、高脂血症和其他内分泌疾病^[30]。近年来, 多项研究表明ASGR1在脂质代谢中扮演着关键角色(图2)。ASGR1功能缺失型变异(如del12及W158X)可显著降低血非高密度脂蛋白胆固醇(non-high density lipoprotein cholesterol, non-HDL-C)水平^[31], 且携带者心血管事件风险降低26%^[32]。ASGR1-LOF变异通过抑制甾醇调节元件结合蛋白(sterol-regulatory element binding protein, SREBP)通路(减少胆固醇合成)和增强低密度脂蛋白受体(low density lipoprotein receptor, LDLR)稳定性[促进低密度脂蛋白胆固醇(low density lipoprotein cholesterol, LDL-C)清除] 实现降脂效应(图2)。此外, Xie等^[33]研究发现ASGR1缺失可抑制胆固醇合成限速酶HMG-CoA还原酶(3-hydroxy-3-methyl glutaryl coenzyme A reductase, HMGCR)的活性, 减少肝脏胆固醇的从头合成, 进一步降低non-HDL-C水平。

在胆固醇外排方面, ASGR1缺失通过抑制雷帕霉素靶蛋白复合体1 (mechanistic target of rapamycin complex 1, mTORC1)并激活AMP依赖的蛋白激酶[adenosine 5'-monophosphate (AMP)-activated protein kinase, AMPK], 下调泛素连接酶乳腺癌易感蛋白1 (breast cancer susceptibility protein-1, BRCA1)或BRCA1关联的RING域1 (BRCA1 associated RING domain 1, BARD1), 进而稳定肝X受体α (liver X receptor α, LXRα), 最终促进胆固醇外排蛋白ATP结合盒转运体G5 (ATP binding cassette subfamily G member 5, ABCG5)和ATP结合盒转运体G8 (ATP binding cassette subfamily G member 8, ABCG8)的表达, 增加胆汁和粪便中胆固醇的排泄^[27]。同时, ASGR1缺失抑制SREBP活性, 减少脂肪酸合成, 改善脂质代谢紊乱^{[27, 34, 35]}。

综上, ASGR1通过调节LDLR、LXRα、HMGCR和SREBP等关键分子, 在胆固醇代谢中发挥核心作用。ASGR1作为治疗高胆固醇血症的新型靶点, 其缺失或抑制展现出显著的降脂和动脉保护效果。但需注意, 胆固醇外排增强导致的胆汁酸合成代偿性上调可能打破胆汁酸池稳态, 引起肝损伤^{[33, 36, 37]}与肝细胞脂质堆积^[38], 因此, 抑制ASGR1以治疗高血脂是否安全有效仍需进一步研究。

4.2　ASGR1与代谢相关脂肪性肝病

代谢相关脂肪性肝病(metabolic associated fatty liver disease, MAFLD)是全球最普遍的慢性肝病, 由国际专家组于2020年提出, 强调以代谢功能障碍为核心, 取代了传统的非酒精性脂肪肝概念^[39]。MAFLD包括从单纯性肝脂肪变性到伴炎症的脂肪性肝病, 并可进展为肝纤维化、肝硬化及肝细胞癌^[40]。ASGR1在其发生发展中具有复杂的功能表现, 既参与肝脏脂质代谢紊乱和炎症反应的调控, 也与肝纤维化及肝硬化的进展密切相关(图2)。

ASGR1通过调控溶酶体氨基酸感知和代谢信号通路, 影响肝脏脂质动态平衡。当ASGR1功能缺失时, 去唾液酸化糖蛋白的内吞和溶酶体降解受阻, 导致溶酶体内氨基酸水平下降, 进而抑制mTORC1信号并激活AMPK^{[27, 35]}。激活的AMPK通过双重机制改善脂质代谢: ①通过抑制转录因子SREBP1c减少脂肪酸和甘油三酯的合成^[26]; ②通过稳定LXRα, 上调胆固醇外排蛋白ABCG5/G8的表达, 促进胆固醇经胆汁排泄, 从而缓解肝脏脂质蓄积^{[27, 41]}。此外, ASGR1缺失可抑制炎症相关通路(如NF-κB), 减少促炎因子的释放, 减轻肝脏炎症微环境^{[36, 42]}。这种抗炎作用进一步通过改善胰岛素敏感性和脂质氧化能力, 协同改善代谢紊乱。

然而, ASGR1缺陷对肝脏稳态的影响存在显著矛盾性。一方面, 其缺失可通过AMPK等通路改善脂质代谢和胰岛素敏感性; 另一方面, 也可能诱导多种有害信号。Zhu等^[43]报道, ASGR1缺陷可显著激活信号转导和转录激活因子3 (signal transducer and activator of transcription 3, STAT3)通路, 导致促炎因子和纤维化相关因子表达升高, 促进慢性炎症和肝纤维化发生。此外, 研究提示nemo样激酶(nemo-like kinase, NLK)可增强STAT3活性, 从而进一步加速纤维化进程。Zhang等^[37]研究表明, ASGR1缺失还可能通过上调GP73表达, 诱导内质网应激反应并加重肝损伤。因此, ASGR1功能丧失可能通过多途径破坏肝脏稳态, 促进纤维化恶性转化。

ASGR1的“双刃剑”机制揭示了其在脂质代谢与炎症调控网络中的重要地位。临床数据显示, MAFLD及肝硬化患者的组织中ASGR1表达显著降低, 其表达水平与疾病严重程度呈负相关^[37]。机制矛盾性(如代谢获益与STAT3驱动的损伤并存)则部分解释了MAFLD向终末期肝病进展的复杂性^[44-47]。值得注意的是, ASGR1还参与促进各类肝炎病毒进入细胞, 如甲型肝炎病毒(hepatitis A virus, HAV)^{[48, 49]}、乙型肝炎病毒(hepatitis B virus, HBV)^{[50, 51]}、丙型肝炎病毒(hepatitis C virus, HCV)^[52]、戊型肝炎病毒(hepatitis E virus, HEV)^[53]及严重急性呼吸综合征冠状病毒2 (severe acute respiratory syndrome coronavirus-2, SARS-CoV-2)^{[54, 55]}, 提示其可能通过调控病毒侵袭性和免疫反应而间接介导肝脏损伤过程^{[56, 57]}。未来靶向ASGR1的治疗策略需精准调控其下游效应分子, 从而在改善代谢的同时规避纤维化风险。

4.3　ASGR1与动脉粥样硬化

动脉粥样硬化是一种慢性炎症性血管疾病, 其病理特征为脂质在动脉内膜异常蓄积, 伴随免疫细胞浸润形成斑块^[58], 已被广泛认定为全球心脑血管疾病主要的病理生理基础^[59]。ASGR1通过多维度调控脂质代谢与炎症反应, 在动脉粥样硬化(atherosclerosis, AS)的病理进程中发挥关键作用(图2)。

脂质代谢环节, ASGR1功能缺失通过抑制微粒体甘油三酯转运蛋白(microsomal triglyceride transfer protein, MTTP)和血管生成素样蛋白3/8 (angiopoietin-like 3/8, ANGPTL3/8)表达, 减少极低密度脂蛋白(very low-density lipoprotein, VLDL)的合成与分泌, 并增强脂蛋白脂肪酶(lipoprotein lipase, LPL)活性以加速甘油三酯的降解, 从而显著降低血浆LDL-C及极低密度脂蛋白胆固醇(very low-density lipoprotein cholesterol, VLDL-C)水平^[38]。上述脂蛋白的减少直接降低脂质在动脉内膜的沉积, 延缓脂纹形成。同时, ASGR1缺失上调肝脏LDLR表达促进LDL清除^[35], 并通过激活AMPK/mTORC1信号轴进一步抑制SREBP介导的脂质合成通路改善脂质谱(如升高HDL-C)^{[27, 34]}, 协同减轻血管壁损伤。

炎症调控方面, 肝细胞ASGR1特异性缺失被报道可通过抑制mTORC1活性减少促炎因子释放^[35], 进而减轻血管内皮炎症反应; 全身性ASGR1缺失则通过上调胆固醇外排蛋白如ATP结合盒转运体A1 (ATP-binding cassette transporter A1, ABCA1)及ABCG5/G8, 促进巨噬细胞胆固醇逆向转运, 减少斑块内泡沫细胞形成及脂质蓄积^[38]。动物实验显示^[38], ASGR1全身敲除可使西方饮食饲养小鼠斑块面积减少大于50%, 血浆总胆固醇和甘油三酯水平显著下降, 证实其抗AS的显著效果。同时进一步研究证明ASGR1功能缺陷通过增强内皮屏障功能, 减少脂质浸润及炎症细胞迁移, 从而抑制斑块进展。

尽管ASGR1作为动脉粥样硬化治疗靶点的潜力已被多项研究证实, 但其临床应用仍面临胆固醇过多排泄及影响肝脏代谢等挑战。

4.4　ASGR1与糖尿病

糖尿病(diabetes mellitus, DM)是一种以血糖升高为主要特征的慢性代谢性疾病, 由不同程度的胰岛素抵抗(insulin resistance, IR)和胰岛素分泌功能障碍引起^[60]。如图2所示, ASGR1可通过调控肝细胞的胰岛素敏感性, 在机体糖代谢稳态中发挥关键作用。Yu等^[61]发现, ASGR1缺陷可激活胰岛素受体底物(insulin receptor substrate, IRS)-磷酸肌醇3激酶(phosphatidylinositol 3-kinase, PI3K)-蛋白激酶B (protein kinase B, AKT)通路, 促进AKT磷酸化, 抑制糖异生关键酶的表达, 从而减少肝脏葡萄糖生成(hepatic glucose production, HGP)并改善系统性胰岛素抵抗; ASGR1缺陷还能上调胰岛素诱导基因1 (insulin-induced gene 1, INSIG1)抑制SREBP的加工与转运, 减少脂肪酸及胆固醇合成从而增强肝脏胰岛素信号。除此之外, 临床数据^[62]显示ASGR1在2型糖尿病合并冠心病患者外周血单核细胞中表达下调, 提示其在代谢紊乱相关疾病中可能存在功能改变, 进一步突显了其在不同代谢环境下功能的复杂性和多面性。因此, ASGR1作为糖脂代谢调控的重要因子, 有望成为代谢性疾病干预的新靶点。

5　ASGR1靶向治疗的临床研究进展

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近年来, ASGR1作为肝脏特异性受体, 其靶向治疗在代谢性疾病及肝病领域受到广泛关注。随着学术界的不断投入, 其抗体类抑制剂和药物递送系统为动脉粥样硬化、代谢相关脂肪性肝病及肝纤维化等疾病的精准治疗提供了新的策略和希望。

5.1　靶向ASGR1的抗体类抑制剂

单克隆抗体是ASGR1抑制剂的主要类型之一。由武汉大学宋保亮团队^[27]开发的4B9抗体能够高亲和力结合ASGR1的胞外结构域, 阻断其与配体的相互作用, 同时与他汀类药物联用可协同抑制胆固醇合成与外排, 进一步优化降脂效果。另一代表性单克隆抗体AMG 529^[63] (由Amgen开发)已完成Ⅰ期临床试验, 数据显示其耐受性良好, 并能剂量依赖性地降低健康受试者的总胆固醇和LDL-C水平, 提示其潜在的临床应用价值(表1)。

双特异性抗体是抗体类抑制剂的重要拓展方向。SZN-043^[64]是一种同时靶向ASGR1和Wnt信号通路相关蛋白的双特异性抗体, 其通过ASGR1介导的肝细胞靶向作用, 激活Wnt/β-catenin信号通路, 其设计基于ASGR1在肝细胞再生^[36]和免疫微环境调节^{[65, 66]}中的双重作用。临床前研究表明, SZN-043在肝纤维化模型中显著减少胶原沉积并改善肝功能, 目前已进入Ⅰ期临床试验, 用于治疗酒精性肝炎和肝硬化。此外, 基于ASGR1识别病原体糖蛋白的天然功能^{[54, 67, 68]}, 免疫偶联物如ASGR1-TLR8偶联物SBT8230^[69]通过靶向递送免疫调节分子至肝脏, 激活局部抗病毒或抗肿瘤免疫反应, 为慢性乙肝和肝癌的治疗提供了新策略。

5.2　靶向ASGR1的药物递送系统

靶向ASGR1的药物递送系统是基于该受体在肝细胞表面特异性高表达的特性而设计的精准治疗策略。ASGR1能够特异性识别并内吞含有Gal或GalNAc的糖蛋白, 这一特性使其成为肝脏靶向递送的理想靶点。

GalNAc共轭递送系统是靶向ASGR1的核心技术之一。GalNAc作为ASGR1的天然配体, 可通过化学偶联与核酸药物[如小干扰RNA (small interfering RNA, siRNA)^[70]、反义寡核苷酸(antisense oligonucleotides, ASO)^[71]或微小RNA (microRNA, miRNA)^[72]] 结合, 形成稳定的复合物。临床药物如siRNA和反义核苷酸等已经通过GalNAc递送系统实现了肝脏靶向治疗(表2)。如Alnylam公司开发的GalNAc-siRNA技术已成功应用于多款获批药物, 包括治疗淀粉样变性多发性神经病的vutrisiran (Amvuttra)^[73]、治疗急性肝卟啉症的givosiran (Givlaari)^{[74, 75]}及靶向前蛋白转化酶枯草溶菌素9 (proprotein convertase subtilisin/kexin type 9, PCSK9)治疗高胆固醇血症的inclisiran (Leqvio)^[76]。这些药物通过ASGR1介导的内吞作用进入肝细胞后, siRNA在胞内释放并沉默靶基因表达, 从而实现对疾病相关通路的精准调控。此外, GalNAc共轭技术还被拓展至CRISPR-Cas9基因编辑系统, 如Intellia Therapeutics开发的NTLA-2001^[77], 其通过GalNAc-LNP递送系统靶向肝脏, 用于治疗遗传性转甲状腺素蛋白淀粉样变性, 目前已进入临床试验阶段。值得注意的是, 虽然目前获批药物主要针对罕见肝病, 但它们验证了GalNAc-ASGR1递送系统在肝脏靶向沉默致病基因的有效性和安全性, 为该系统应用于更广泛的代谢性疾病如高胆固醇血症、代谢相关脂肪性肝病、2型糖尿病奠定了坚实基础。

尽管靶向ASGR1的递送系统在肝病治疗中展现出显著优势, 其临床应用仍面临递送速率^[24]、受体脱敏^{[27, 37]}和生物相容性^[78]等问题。未来研究需聚焦于开发新型配体, 探索多靶点协同递送策略, 并结合人工智能技术优化递送系统设计。随着基因编辑和核酸药物技术的快速发展, 靶向ASGR1的递送系统有望在精准医学领域实现更广泛的应用。

6　结语与展望

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综上所述, ASGR1作为肝脏细胞重要膜受体, 在代谢疾病中发挥着糖蛋白识别、脂质代谢调节及免疫调控等重要作用, 相关分子调节机制涉及多种信号通路和调控因子, 其功能的改变与多种代谢性疾病的发展密切相关, 同时基于ASGR1的递送系统也为肝靶向治疗提供了新的思路和方向。

尽管已有研究显示, ASGR1缺陷在部分疾病模型中表现出保护作用, 但也有研究提示其在其他代谢紊乱状态下可能加重病情, 这种功能的双重性提示ASGR1在不同疾病模型和病理阶段中可能具有不同的生物学效应。因此, 未来研究应聚焦于ASGR1在组织特异性表达与时序性调控等维度的机制解析, 并探索相应的精准干预策略, 为ASGR1相关靶向药物的研发与优化提供理论基础与实践指导。

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2026年第61卷第1期

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doi: 10.16438/j.0513-4870.2025-0731

接收时间：2025-06-26
首发时间：2026-09-21
出版时间：2026-01-12

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收稿日期：2025-06-26
修回日期：2025-09-01

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中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050

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雷蕾, Tel: 86-10-63165194, E-mail: dlei228@imm.ac.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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