肝巨噬细胞在代谢相关脂肪性肝病中的作用机制及相关靶向治疗策略

肖蕾; 沙婉婷; 吴嘉雯; 杨梅; 赵琦; 李开楊

doi:10.12449/JCH260924

肝巨噬细胞在代谢相关脂肪性肝病中的作用机制及相关靶向治疗策略

DOI: 10.12449/JCH260924

肖蕾¹,
沙婉婷¹,
吴嘉雯¹,
杨梅^2, , ,,
赵琦³,
李开楊¹

1.
贵州中医药大学第二临床医学院，贵阳 550002
2.
贵州中医药大学第二附属医院检验科，贵阳 550001
3.
贵州中医药大学第二附属医院消化内科，贵阳 550001

基金项目:

国家自然科学基金 (82160866);

2024年贵州中医药大学“青年扬帆计划”项目 (Guizhongyikehe-QNYFZK ［2024］ No.12)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：肖蕾负责选题及撰写论文；沙婉婷、吴嘉雯和李开楊负责查找文献及修改论文；赵琦负责拟定思路；杨梅负责指导撰写文章。

详细信息

通信作者:
杨梅， 908417289@qq.com （ORCID： 0009-0003-3563-4767）

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出版历程
- 收稿日期: 2026-01-02
- 录用日期: 2026-03-02
- 出版日期: 2026-09-25

Mechanism of action of hepatic macrophages in metabolic dysfunction-associated fatty liver disease and related targeted therapeutic strategies

1.
The Second Clinical Medical School of Guizhou University of Traditional Chinese Medicine，Guiyang 550002，China
2.
Department of Clinical Laboratory，The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine，Guiyang 550001，China
3.
Department of Gastroenterology，The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine，Guiyang 550001，China

Research funding:

National Natural Science Foundation of China (82160866);

2024 “Youth Sailing Program” Project of Guizhou University of Traditional Chinese Medicine (Guizhongyikehe-QNYFZK ［2024］ No.12)

More Information

Corresponding author: Yang Mei， 908417289@qq.com （ORCID： 0009-0003-3563-4767）

摘要

摘要: 代谢相关脂肪性肝病（MAFLD）是目前全球最常见的慢性肝病，其疾病谱包括单纯性脂肪肝、代谢相关脂肪性肝炎、肝纤维化、肝硬化和肝细胞癌。近年来研究揭示，肝巨噬细胞在MAFLD发生发展中发挥重要调控作用。肝巨噬细胞主要包括定居肝脏的库普弗细胞和单核来源的巨噬细胞，通过调节炎症反应、脂质代谢、纤维化进程和细胞死亡途径，参与疾病的病理生理过程。本文综述了肝巨噬细胞在MAFLD中的类型多样性、功能可塑性及其与肝细胞、肠道微生物之间的相互作用，重点阐述了肝巨噬细胞及相关信号通路在MAFLD进展中的核心机制，并探讨了以肝巨噬细胞为靶点的新型治疗策略。深入理解肝巨噬细胞在MAFLD中的作用机制，可为开发MAFLD的精准治疗方法提供重要理论基础。
- 代谢相关脂肪性肝病 /
- 巨噬细胞 /
- 病理过程 /
- 分子靶向治疗
Abstract: Metabolic dysfunction-associated fatty liver disease （MAFLD） is currently the most prevalent chronic liver disease worldwide， and its disease spectrum encompasses simple steatosis， metabolic-associated steatohepatitis， hepatic fibrosis， liver cirrhosis， and hepatocellular carcinoma. Recent studies have shown that hepatic macrophages play an important regulatory role in the development and progression of MAFLD. Hepatic macrophages mainly consist of resident Kupffer cells and monocyte-derived macrophages， which participate in the pathophysiological processes of the disease by regulating inflammatory response， lipid metabolism， fibrogenic process， and cell death pathways. This article summarizes the diversity and functional plasticity of hepatic macrophages in MAFLD， reviews their interactions with hepatocytes and gut microbiota， elaborates on the core mechanism of hepatic macrophages and related signaling pathways in the progression of MAFLD， and further discusses novel therapeutic strategies targeting hepatic macrophages. An in-depth understanding of the mechanism of action of hepatic macrophages in MAFLD may provide a crucial theoretical basis for developing precise therapeutic approaches for this disease.
- Metabolic Dysfunction-Associated Fatty Liver Disease /
- Macrophages /
- Pathologic Processes /
- Molecular Targeted Therapy

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注： a，肝巨噬细胞M1/M2极化平衡及亚型分化调控示意图；b，下游信号通路调控机制示意图。CLEC4F，C型凝集素结构域家族4成员F；CD11b，分化簇11b；F4/80，F4/80分子；Th1，辅助性T细胞1；Th2，辅助性T细胞2；IL，白细胞介素；IC，免疫复合物；LPS，脂多糖；IFN-γ，干扰素γ；GM-CSF，粒细胞-巨噬细胞集落刺激因子；CD163，分化簇163；CD86，分化簇86；CD36，分化簇36；CD206，分化簇206；CD80，分化簇80；STAT，信号转导与转录激活因子；IL-1R，白细胞介素1受体；TLR，Toll样受体；A2R，A2腺苷受体；TGF-β，转化生长因子β；MR，甘露糖受体；CCL17，CC亚族趋化因子配体17；CCL2，CC亚族趋化因子配体2；CCL1，CC亚族趋化因子配体1；CXCL9，C-X-C基序趋化因子配体9；CX3CL1，C-X3-C基序趋化因子配体1；FOXO1，叉头框蛋白O1；IGF，胰岛素样生长因子；TNFSF14，肿瘤坏死因子超家族成员14；MerTK，Mer受体酪氨酸激酶；VEGF，血管内皮生长因子；NF-κB，核因子κB；Wnt/β-catenin，无翼样糖蛋白/β-联蛋白通路；PI3K/Akt/mTOR，磷脂酰肌醇3-激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白通路；MIF-CD74，巨噬细胞迁移抑制因子-分化簇74轴；E2F2-SLC7A5-mTORC1，叉头框蛋白E2-溶质载体家族7成员5-哺乳动物雷帕霉素靶蛋白复合物1轴；PPAR，过氧化物酶体增殖物激活受体；MyD88，髓样分化因子88；TNF-α，肿瘤坏死因子α；MoMF，骨髓来源的单核巨噬细胞；TREM，髓样细胞触发受体；Smad，母系抗十五表态蛋白同源物；MAFLD，代谢相关脂肪性肝病；MAFL，代谢相关单纯性脂肪肝；MASH，代谢相关脂肪性肝炎；HCC，肝细胞癌。

图 1 肝巨噬细胞及相关信号通路在MAFLD进展中的作用机制

Figure 1. Roles and mechanisms of hepatic macrophages and associated signaling pathways in MAFLD progression

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表 1 2024—2025年肝巨噬细胞靶向治疗MAFLD的策略

Table 1. Hepatic macrophage-related therapeutic strategies for MAFLD （2024—2025）

疾病领域	策略	核心机制	研发阶段
MASH	M2巨噬细胞仿生纳米递药平台（O^@OLGA^@M）	利用M2膜炎症趋化性靶向递送奥贝胆酸，重编程M1→ M2，协同调节脂代谢、抗炎和抗纤维化，并调控肠道菌群^［15］	临床前（2025-09-25报道）
HCC	仿生靶向铁死亡纳米平台（Sv^@PM-M2p）	同时靶向肝癌细胞与M2型TAM，诱导双重铁死亡，逆转免疫抑制，重塑肿瘤微环境^［58］	临床前（2025-11-24报道）
肝纤维化/ 肝硬化	CAR-Ms（靶向uPAR）	CAR-Ms特异性归巢肝脏，调节免疫微环境，促进中性粒细胞和M2型巨噬细胞浸润，激活抗纤维化T细胞反应，减轻纤维化^［63］	临床前（2024-10-02报道）
	自体工程巨噬细胞（RTX001）（国外）	自体巨噬细胞经工程化改造，具有抗炎、抗纤维化功能，用于终末期肝病患者的细胞疗法^［61］	Ⅰ/Ⅱ期临床（2025-10-02 报道）
	自体工程巨噬细胞（MACF-001）（国内）	采用自主知识产权的抗纤维化Payloads组合与递送系统，维持巨噬细胞免疫修复表型^［62］	早期临床研究中
	非工程巨噬细胞（MATCH实验）	单剂量自体巨噬细胞输注后，67%患者的肝纤维化评分改善≥1级，MELD评分显著降低，无严重不良反应^［64］	Ⅱ期临床（2025-03-01 报道）
	自体单核细胞来源巨噬细胞输注	在代偿期肝硬化患者中显示安全性，并呈现抗炎潜力（降低促炎因子、提升抗炎因子）	Ⅱ期临床（2025-01-13 报道）
注：MAFLD，代谢相关脂肪性肝病；MASH，代谢相关脂肪性肝炎；HCC，肝细胞癌；CAR-Ms，嵌合抗原受体修饰巨噬细胞；uPAR，尿激酶型纤溶酶原激活物受体；RTX001，自体工程巨噬细胞（国外）；MACF-001，自体工程巨噬细胞（国内）；MELD，终末期肝病模型；O^@OLGA^@M，M2巨噬细胞仿生纳米递药平台；Sv^@PM-M2p，仿生靶向铁死亡纳米平台；TAM，肿瘤相关巨噬细胞。

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