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

Lei Xiao; Wanting Sha; Jiawen Wu; Mei Yang; Qi Zhao; Kaiyang Li

doi:10.12449/JCH260924

Volume 42 Issue 9

Sep. 2026

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Article Navigation > Journal of Clinical Hepatology > 2026 > 42(9): 2183-2190

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

DOI: 10.12449/JCH260924

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）
Received Date: 2026-01-02
Accepted Date: 2026-03-02
Published Date: 2026-09-25

Abstract

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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References

[1]	Estes C, Chan H L Y, Chien R N, et al. Modelling NAFLD disease burden in four Asian regions: 2019-2030[J]. Aliment Pharmacol Ther, 2020, 51( 8): 801- 811. DOI: 10.1111/apt.15673.
[2]	Sandireddy R, Sakthivel S, Gupta P, et al. Systemic impacts of metabolic dysfunction-associated steatotic liver disease(MASLD) and metabolic dysfunction-associated steatohepatitis(MASH) on heart, muscle, and kidney related diseases[J]. Front Cell Dev Biol, 2024, 12: 1433857. DOI: 10.3389/fcell.2024.1433857.
[3]	González-Serrano S, Onoiu A I, Camps J, et al. Immunometabolic integration in therapeutic strategies for managing MASLD[J]. Front Pharmacol, 2025, 16: 1693753. DOI: 10.3389/fphar.2025.1693753.
[4]	Krenkel O, Hundertmark J, Abdallah A T, et al. Myeloid cells in liver and bone marrow acquire a functionally distinct inflammatory phenotype during obesity-related steatohepatitis[J]. Gut, 2020, 69( 3): 551- 563. DOI: 10.1136/gutjnl-2019-318382.
[5]	Orci L A, Kreutzfeldt M, Goossens N, et al. Tolerogenic properties of liver macrophages in non-alcoholic steatohepatitis[J]. Liver Int, 2020, 40( 3): 609- 621. DOI: 10.1111/liv.14336.
[6]	Scott C L, Zheng F, de Baetselier P, et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells[J]. Nat Commun, 2016, 7: 10321. DOI: 10.1038/ncomms10321.
[7]	Sierro F, Evrard M, Rizzetto S, et al. A liver capsular network of monocyte-derived macrophages restricts hepatic dissemination of intraperitoneal bacteria by neutrophil recruitment[J]. Immunity, 2017, 47( 2): 374- 388. e 6. DOI: 10.1016/j.immuni.2017.07.018.
[8]	Gomez Perdiguero E, Klapproth K, Schulz C, et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors[J]. Nature, 2015, 518( 7540): 547- 551. DOI: 10.1038/nature13989.
[9]	He Y, Chen Y F, Qian S Y, et al. Immunopathogenic mechanisms and immunoregulatory therapies in MASLD[J]. Cell Mol Immunol, 2025, 22( 10): 1159- 1177. DOI: 10.1038/s41423-025-01307-5.
[10]	Devisscher L, Scott C L, Lefere S, et al. Non-alcoholic steatohepatitis induces transient changes within the liver macrophage pool[J]. Cell Immunol, 2017, 322: 74- 83. DOI: 10.1016/j.cellimm.2017.10.006.
[11]	Viola A, Munari F, Sánchez-Rodríguez R, et al. The metabolic signature of macrophage responses[J]. Front Immunol, 2019, 10: 1462. DOI: 10.3389/fimmu.2019.01462.
[12]	Wang L X, Zhang S X, Wu H J, et al. M2b macrophage polarization and its roles in diseases[J]. J Leukoc Biol, 2019, 106( 2): 345- 358. DOI: 10.1002/JLB.3RU1018-378RR.
[13]	Cui C, Gao S, Shi J F, et al. Gut-liver axis: The role of intestinal microbiota and their metabolites in the progression of metabolic dysfunction-associated steatotic liver disease[J]. Gut Liver, 2025, 19( 4): 479- 507. DOI: 10.5009/gnl240539.
[14]	Miyamoto Y, Kikuta J, Matsui T, et al. Periportal macrophages protect against commensal-driven liver inflammation[J]. Nature, 2024, 629( 8013): 901- 909. DOI: 10.1038/s41586-024-07372-6.
[15]	Pan X E, Chen X Y, Ma Y, et al. Chemotaxis-guided nanoplatform for non-alcoholic steatohepatitis therapy via macrophage reprogramming, hepatoprotection and gut microbiome modulation[J]. Biomaterials, 2026, 326: 123694. DOI: 10.1016/j.biomaterials.2025.123694.
[16]	de Muynck K, Vanderborght B, van Vlierberghe H, et al. The gut-liver axis in chronic liver disease: A macrophage perspective[J]. Cells, 2021, 10( 11): 2959. DOI: 10.3390/cells10112959.
[17]	Balmer M L, Slack E, de Gottardi A, et al. The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota[J]. Sci Transl Med, 2014, 6( 237): 237ra66. DOI: 10.1126/scitranslmed.3008618.
[18]	di Ciaula A, Baj J, Garruti G, et al. Liver steatosis, gut-liver axis, microbiome and environmental factors. A never-ending bidirectional cross-talk[J]. J Clin Med, 2020, 9( 8): 2648. DOI: 10.3390/jcm9082648.
[19]	Yi Z F, Fan H, Liu X X, et al. Adrenomedullin improves intestinal epithelial barrier function by downregulating myosin light chain phosphorylation in ulcerative colitis rats[J]. Mol Med Rep, 2015, 12( 3): 3615- 3620. DOI: 10.3892/mmr.2015.3887.
[20]	Rizvi F, Everton E, Smith A R, et al. Murine liver repair via transient activation of regenerative pathways in hepatocytes using lipid nanoparticle-complexed nucleoside-modified mRNA[J]. Nat Commun, 2021, 12: 613. DOI: 10.1038/s41467-021-20903-3.
[21]	Hendrikx T, Porsch F, Kiss M G, et al. Soluble TREM2 levels reflect the recruitment and expansion of TREM2(+) macrophages that localize to fibrotic areas and limit NASH[J]. J Hepatol, 2022, 77( 5): 1373- 1385. DOI: 10.1016/j.jhep.2022.06.004.
[22]	Li L, Cui L, Lin P, et al. Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers[J]. Cell Stem Cell, 2023, 30( 3): 283- 299.e9. DOI: 10.1016/j.stem.2023.01.009.
[23]	del Mar Rigual M, Angulo-Aguado M, Zagorac S, et al. Macrophages harness hepatocyte glutamate to boost liver regeneration[J]. Nature, 2025, 641( 8064): 1005- 1016. DOI: 10.1038/s41586-025-08778-6.
[24]	Wang H Y, Poulain S, Cao W X, et al. Palmitic acid induced the onset of lipotoxicity in a HepaSH-on-chip model with raised of H₂O₂ and IL-6, and altered p38/MAPK& JAK/STAT pathways[J]. Toxicology, 2026, 520: 154345. DOI: 10.1016/j.tox.2025.154345.
[25]	Xu X, Li H G, Lin H, et al. MIF-mediated crosstalk between THRSP⁺ hepatocytes and CD74⁺lipid-associated macrophages in hepatic periportal zone drives MASH[J]. Hepatology, 2026, 83( 4): 868- 887. DOI: 10.1097/HEP.0000000000001429.
[26]	Xu R N, Vujić N, Bianco V, et al. Lipid-associated macrophages between aggravation and alleviation of metabolic diseases[J]. Trends Endocrinol Metab, 2024, 35( 11): 981- 995. DOI: 10.1016/j.tem.2024.04.009.
[27]	Tian Y X, Ni Y M, Zhang T, et al. Targeting hepatic macrophages for non-alcoholic fatty liver disease therapy[J]. Front Cell Dev Biol, 2024, 12: 1444198. DOI: 10.3389/fcell.2024.1444198.
[28]	Lumeng C N, Bodzin J L, Saltiel A R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization[J]. J Clin Invest, 2007, 117( 1): 175- 184. DOI: 10.1172/JCI29881.
[29]	Wang J J, Cai Y, Feng Y X, et al. Diabetic kidney disease macrophage cholesterol efflux: A revolution from metabolism to immune[J]. Front Endocrinol, 2025, 16: 1714167. DOI: 10.3389/fendo.2025.1714167.
[30]	Shi S Y, Zhou Y Y, Zhang H M, et al. TREM2 in MASH: Integrating lipid metabolism and immune response[J]. Front Immunol, 2025, 16: 1604837. DOI: 10.3389/fimmu.2025.1604837.
[31]	Perugorria M J, Esparza-Baquer A, Oakley F, et al. Non-parenchymal TREM-2 protects the liver from immune-mediated hepatocellular damage[J]. Gut, 2019, 68( 3): 533- 546. DOI: 10.1136/gutjnl-2017-314107.
[32]	Indira Chandran V, Wernberg C W, Lauridsen M M, et al. Circulating TREM2 as a noninvasive diagnostic biomarker for NASH in patients with elevated liver stiffness[J]. Hepatology, 2023, 77( 2): 558- 572. DOI: 10.1002/hep.32620.
[33]	Song K, Kwon H, Han C, et al. Yes-associated protein in kupffer cells enhances the production of proinflammatory cytokines and promotes the development of nonalcoholic steatohepatitis[J]. Hepatology, 2020, 72( 1): 72- 87. DOI: 10.1002/hep.30990.
[34]	Zou Xuchen, Chen Qian, Shi Chunxia, et al. Effect of macrophage migration inhibitory factor on liver inflammation in mice with acute liver failure[J]. J Med Res, 2024, 53( 5): 38- 41, 47. DOI: 10.11969/j.issn.1673-548X.2024.05.009. 邹旭晨, 陈倩, 石春霞, 等. 巨噬细胞移动抑制因子在急性肝衰竭小鼠肝脏炎症中的作用研究[J]. 医学研究杂志, 2024, 53( 5): 38- 41, 47. DOI: 10.11969/j.issn.1673-548X.2024.05.009.
[35]	Tacke F. Targeting hepatic macrophages to treat liver diseases[J]. J Hepatol, 2017, 66( 6): 1300- 1312. DOI: 10.1016/j.jhep.2017.02.026.
[36]	Zhang J, Wang Y, Fan M Y, et al. Reactive oxygen species regulation by NCF1 governs ferroptosis susceptibility of Kupffer cells to MASH[J]. Cell Metab, 2024, 36( 8): 1745- 1763. e 6. DOI: 10.1016/j.cmet.2024.05.008.
[37]	Valenti L, Moscatiello S, Vanni E, et al. Venesection for non-alcoholic fatty liver disease unresponsive to lifestyle counselling: A propensity score-adjusted observational study[J]. QJM, 2011, 104( 2): 141- 149. DOI: 10.1093/qjmed/hcq170.
[38]	Tsurusaki S, Tsuchiya Y, Koumura T, et al. Hepatic ferroptosis plays an important role as the trigger for initiating inflammation in nonalcoholic steatohepatitis[J]. Cell Death Dis, 2019, 10: 449. DOI: 10.1038/s41419-019-1678-y.
[39]	Pierantonelli I, Svegliati-Baroni G. Nonalcoholic fatty liver disease: Basic pathogenetic mechanisms in the progression from NAFLD to NASH[J]. Transplantation, 2019, 103( 1): e1- e13. DOI: 10.1097/TP.0000000000002480.
[40]	Yi Z H, Li S Q, Ke J Y, et al. Baicalein relieves ferroptosis-mediated phagocytosis inhibition of macrophages in ovarian endometriosis[J]. Curr Issues Mol Biol, 2022, 44( 12): 6189- 6204. DOI: 10.3390/cimb44120422.
[41]	Kohlhepp M S, Liu H Y, Tacke F, et al. The contradictory roles of macrophages in non-alcoholic fatty liver disease and primary liver cancer-Challenges and opportunities[J]. Front Mol Biosci, 2023, 10: 1129831. DOI: 10.3389/fmolb.2023.1129831.
[42]	Guillot A, Winkler M, Silva Afonso M, et al. Mapping the hepatic immune landscape identifies monocytic macrophages as key drivers of steatohepatitis and cholangiopathy progression[J]. Hepatology, 2023, 78( 1): 150- 166. DOI: 10.1097/HEP.0000000000000270.
[43]	Guo W, Li Z Y, Anagnostopoulos G, et al. Notch signaling regulates macrophage-mediated inflammation in metabolic dysfunction-associated steatotic liver disease[J]. Immunity, 2024, 57( 10): 2310- 2327. e 6. DOI: 10.1016/j.immuni.2024.08.016.
[44]	Guillot A, Tacke F. Spatial dimension of macrophage heterogeneity in liver diseases[J]. eGastroenterology, 2023, 1( 1): e000003. DOI: 10.1136/egastro-2023-000003.
[45]	Ma Simin, Zhu Hanxiao, Li Yuqing, et al. Research progress of THR-β agonists in the treatment of MASH[J]. Acta Pharm Sin, 2025, 60( 9): 2690- 2701. DOI: 10.16438/j.0513-4870.2025-0137. 马思敏, 朱含笑, 李昱晴, 等. THR-β激动剂在非酒精性脂肪肝炎治疗方面的研究进展[J]. 药学学报, 2025, 60( 9): 2690- 2701. DOI: 10.16438/j.0513-4870.2025-0137.
[46]	Kholodenko I V, Yarygin K N. Hepatic macrophages as targets for the MSC-based cell therapy in non-alcoholic steatohepatitis[J]. Biomedicines, 2023, 11( 11): 3056. DOI: 10.3390/biomedicines11113056.
[47]	Obata Y, Abe K, Miyazaki M, et al. The transfer of the hepatocyte growth factor gene by macrophages ameliorates the progression of peritoneal fibrosis in mice[J]. Int J Mol Sci, 2023, 24( 8): 6951. DOI: 10.3390/ijms24086951.
[48]	Peiseler M, Schwabe R, Hampe J, et al. Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease-novel insights into cellular communication circuits[J]. J Hepatol, 2022, 77( 4): 1136- 1160. DOI: 10.1016/j.jhep.2022.06.012.
[49]	Niu Yuanyuan, Wang Longde, Xu Wenjuan, et al. Research progress in the role of M1/M2 polarization of macrophages in different liver diseases[J]. J Shanghai Jiao Tong Univ Med Sci, 2024, 44( 4): 509- 517. DOI: 10.3969/j.issn.1674-8115.2024.04.012. 牛媛媛, 汪龙德, 胥文娟, 等. 巨噬细胞M1/M2型极化在不同肝病中的作用研究进展[J]. 上海交通大学学报(医学版), 2024, 44( 4): 509- 517. DOI: 10.3969/j.issn.1674-8115.2024.04.012.
[50]	Wang Yuhang, Chen Zhiming, Yin Yucheng, et al. Radiotherapy sensitivity regulation of tumor-associated macrophages[J]. Trauma and Crit Medicine, 2024, 12( 3): 182- 185, 190. DOI: 10.16048/j.issn.2095-5561.2024.03.13. 王禹杭, 陈志明, 殷雨成, 等. 肿瘤相关巨噬细胞放射治疗敏感性调节机制与应用进展[J]. 创伤与急危重病医学, 2024, 12( 3): 182- 185,190. DOI: 10.16048/j.issn.2095-5561.2024.03.13.
[51]	Xia Anliang, Sun Beicheng. Research progress of macrophages in non-alcoholic fatty liver diseases[J]. J Nanjing Med Univ Nat Sci, 2023, 43( 10): 1456- 1463. DOI: 10.7655/NYDXBNS20231020. 夏安亮, 孙倍成. 巨噬细胞参与非酒精性脂肪性肝病的研究进展[J]. 南京医科大学学报(自然科学版), 2023, 43( 10): 1456- 1463. DOI: 10.7655/NYDXBNS20231020.
[52]	Nair B, Nath L R. Inevitable role of TGF-β1 in progression of nonalcoholic fatty liver disease[J]. J Recept Signal Transduct Res, 2020, 40( 3): 195- 200. DOI: 10.1080/10799893.2020.1726952.
[53]	Liu Z, Wang H, Liang Y, et al. E2F2 reprograms macrophage function by modulating material and energy metabolism in the progression of metabolic dysfunction-associated steatohepatitis[J]. Adv Sci, 2024, 11( 48): 2410880. DOI: 10.1002/advs.202410880.
[54]	Wree A, Eguchi A, McGeough M D, et al. NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice[J]. Hepatology, 2014, 59( 3): 898- 910. DOI: 10.1002/hep.26592.
[55]	Liu Aifang, Luo Lei, Yang Wenlong. Advances of clinical trials related to Resmetirom as an approved new drug for metabolic dysfunction-associated steatohepatitis[J]. J Clin Hepatol, 2025, 41( 1): 145- 150. DOI: 10.12449/JCH250122. 刘爱芳, 罗磊, 杨文龙. 瑞美替罗(Resmetirom)治疗代谢相关脂肪性肝炎的临床试验进展[J]. 临床肝胆病杂志, 2025, 41( 1): 145- 150. DOI: 10.12449/JCH250122.
[56]	Lai J Q, Zhao L L, Hong C, et al. Baicalein triggers ferroptosis in colorectal cancer cells via blocking the JAK2/STAT3/GPX4 axis[J]. Acta Pharmacol Sin, 2024, 45( 8): 1715- 1726. DOI: 10.1038/s41401-024-01258-z.
[57]	Niu Chunyan, Zhao Xiangyang. Hepatic macrophage-targeted therapy for fatty liver disease: Opportunities and challenges[J]. J Clin Hepatol, 2020, 36( 6): 1393- 1397. DOI: 10.3969/j.issn.1001-5256.2020.06.045. 牛春燕, 赵向阳. 肝巨噬细胞靶向治疗脂肪性肝病及相关肝癌的机遇与挑战[J]. 临床肝胆病杂志, 2020, 36( 6): 1393- 1397. DOI: 10.3969/j.issn.1001-5256.2020.06.045.
[58]	Tang C Y, He C, Wang D C, et al. Co-delivery of sorafenib and an FSP1 inhibitor triggers dual ferroptosis in tumor cells and immunosuppressive macrophages for enhanced immunotherapy in mouse models of hepatocellular carcinoma[J]. Nat Commun, 2025, 16( 1): 10096. DOI: 10.1038/s41467-025-65056-9.
[59]	Chen Y N, Hu M R, Wang L, et al. Macrophage M1/M2 polarization[J]. Eur J Pharmacol, 2020, 877: 173090. DOI: 10.1016/j.ejphar.2020.173090.
[60]	Zhao Y, Ye W L, Wang Y D, et al. HGF/c-met: A key promoter in liver regeneration[J]. Front Pharmacol, 2022, 13: 808855. DOI: 10.3389/fphar.2022.808855.
[61]	Brass C E A. RTX001:An engineered autologous macrophage cell therapy for end-stage liver disease[C]// EASL Congress 2024. Milan, 2024.
[62]	Nanjing Biomedical Valley. Yuanmai Cell, the first domestically engineered macrophage therapy for liver cirrhosis, has achieved clinical breakthroughs[EB/OL].( 2025-10-17)[ 2025-10-25]. https://www.njbpv.cn/index.php?m=content&c=index&a=show&catid=15&id=7970. https://www.njbpv.cn/index.php?m=content&c=index&a=show&catid=15&id=7970 南京生物医药谷. 元迈细胞国内首个工程化巨噬细胞治疗肝硬化临床获突破[EB/OL].( 2025-10-17)[ 2025-10-25]. https://www.njbpv.cn/index.php?m=content&c=index&a=show&catid=15&id=7970. https://www.njbpv.cn/index.php?m=content&c=index&a=show&catid=15&id=7970
[63]	Dai H R, Zhu C, Huai Q, et al. Chimeric antigen receptor-modified macrophages ameliorate liver fibrosis in preclinical models[J]. J Hepatol, 2024, 80( 6): 913- 927. DOI: 10.1016/j.jhep.2024.01.034.
[64]	Brennan P N, MacMillan M, Manship T, et al. Autologous macrophage therapy for liver cirrhosis: A phase 2 open-label randomized controlled trial[J]. Nat Med, 2025, 31( 3): 979- 987. DOI: 10.1038/s41591-024-03406-8.

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

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

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