Therapeutic targeting of myeloid cells in liver fibrosis: Mechanisms and clinical prospects

Abstract

Liver fibrosis, a hallmark pathological endpoint of chronic aging-related liver diseases, remains a clinical challenge with limited therapeutic options. In healthy liver, myeloid cells constitute <5% of total hepatic immune cells, primarily comprising tissue-resident Kupffer cells. However, during aging or chronic injury, bone marrow–derived myeloid cell recruitment increases by two- to threefold in murine fibrotic models, reaching 15%–20% of intrahepatic immune populations. These infiltrating myeloid subsets exhibit functional plasticity, dynamically differentiating into pro-inflammatory macrophages or fibrosis-promoting Kupffer-like cells, contingent upon chemokine gradients (e.g., CCL2/CCR2 axis) and damage-associated molecular patterns (DAMPs). This review systematically examines the regulatory mechanisms of myeloid cells in liver fibrogenesis, with particular emphasis on their developmental origins, hepatic recruitment dynamics, functional heterogeneity, and pathogenic contributions to fibrosis. Furthermore, signaling pathways involving myeloid cells in liver fibrosis and therapeutic approaches modulating their differentiation and recruitment are discussed in this review.

Keywords

aging / hematopoiesis / immune microenvironment / liver fibrosis / myeloid cells

References

[1] Tham EKJ, Tan DJH, Danpanichkul P, et al. The global burden of cirrhosis and other chronic liver diseases in 2021. Liver Int. 2025; 45(3): e70001.

[2] Younossi ZM, Wong G, Anstee QM, Henry L. The global burden of liver disease. Clin Gastroenterol Hepatol. 2023; 21(8): 1978-1991.

[3] Mederacke I, Hsu CC, Troeger JS, et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun. 2013; 4: 2823.

[4] European Association for the Study of the Liver. EASL clinical practice guidelines on liver transplantation. J Hepatol. 2024; 81(6): 1040-1086.

[5] Huang DQ, Mathurin P, Cortez-Pinto H, Loomba R. Global epidemiology of alcohol-associated cirrhosis and HCC: trends, projections and risk factors. Nat Rev Gastroenterol Hepatol. 2023; 20(1): 37-49.

[6] Liu S, Chen X, Jiang X, et al. LiverRisk score: an accurate, cost-effective tool to predict fibrosis, liver-related, and diabetes-related mortality in the general population. Fortschr Med. 2024; 5(6): 570-582.

[7] GBD 2021 Demographics Collaborators. Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950-2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the global burden of disease study 2021. Lancet. 2024; 403(10440): 1989-2056.

[8] Han H, Ge X, Komakula SSB, et al. Macrophage-derived Osteopontin (SPP1) protects from nonalcoholic steatohepatitis. Gastroenterology. 2023; 165(1): 201-217.

[9] 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. Hepatology. 2023; 78(1): 150-166.

[10] Cui A, Li B, Wallace MS, et al. Single-cell atlas of the liver myeloid compartment before and after cure of chronic viral hepatitis. J Hepatol. 2024; 80(2): 251.

[11] Peiseler M, Schwabe RF, Hampe J, et al. Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease - novel insights into cellular communication circuits. J Hepatol. 2022; 77(4): 1136-1160.

[12] Wei Q, Frenette PS. Niches for hematopoietic stem cells and their progeny. Immunity. 2018; 48(4): 632-648.

[13] Morrison SJ, Scadden DT. The bone marrow niche for haematopoietic stem cells. Nature. 2014; 505(7483): 327-334.

[14] Hou J, Chen K-X, He C, et al. Aged bone marrow macrophages drive systemic aging and age-related dysfunction via extracellular vesicle-mediated induction of paracrine senescence. Nat Aging. 2024; 4(11): 1562.

[15] Li Z, Zhang Z, Ren Y, et al. Aging and age-related diseases: from mechanisms to therapeutic strategies. Biogerontology. 2021; 22(2): 165-187.

[16] Liberale L, Badimon L, Montecucco F, Lüscher TF, Libby P, Camici GG. Inflammation, aging, and cardiovascular disease JACC review topic of the week. J Am Coll Cardiol. 2022; 79(8): 837-847.

[17] Fekete M, Major D, Feher A, Fazekas-Pongor V, Lehoczki A. Geroscience and pathology: a new frontier in understanding age-related diseases. Pathol Oncol. 2024; 30: 1611623.

[18] Singh A, Chia JJ, Rao DS, Hoffmann A. Population dynamics modeling reveals that myeloid bias involves both HSC differentiation and progenitor proliferation biases. Blood. 2025; 145(12): 1293-1308.

[19] Farhat A, Radhouani M, Deckert F, et al. An aging bone marrow exacerbates lung fibrosis by fueling profibrotic macrophage persistence. Sci Immunol. 2025; 10(105): eadk5041.

[20] Wang H, Divaris K, Pan B, et al. Clonal hematopoiesis driven by mutated DNMT3A bone loss. Cell. 2024; 187(14): 3690-3711.

[21] Vlasschaert C, Robinson-Cohen C, Chen J, et al. Clonal hematopoiesis of indeterminate potential is associated with acute kidney injury. Nat Med. 2024; 30(3): 810.

[22] Abplanalp WT, Cremer S, John D, et al. Clonal hematopoiesis-driver DNMT3A mutations Alter immune cells in heart failure. Circ Res. 2021; 128(2): 216-228.

[23] Park MD, Le Berichel J, Hamon P, et al. Hematopoietic aging promotes cancer by fueling IL-1α-driven emergency myelopoiesis. Science. 2024; 386(6720): eadn0327.

[24] Leavens KF, Alvarez-Dominguez JR, Vo LT, et al. Stem cell-based multi-tissue platforms to model human autoimmune diabetes. Mol Metab. 2022; 66: 101610.

[25] Wu W, Parks-Schenck C, Guo T, et al. Heterogeneity of single cells obtained from peripheral blood mononuclear cells collected from youth with recent-onset type 1 diabetes. Diabetes. 2023; 72: 217-LB.

[26] Wong WJ, Emdin C, Bick AG, et al. Clonal haematopoiesis and risk of chronic liver disease. Nature. 2023; 616(7958): 747-754.

[27] Yoon J, Jeong M, Park J-H. Intratumoral adoptive transfer of inflammatory macrophages engineered by co-activating TLR and STING signaling pathways exhibits robust antitumor activity. Clin Exp Med. 2023; 23(8): 5025-5037.

[28] Ouyang Y, Nauwynck HJ. PCV2 uptake by porcine monocytes is strain-dependent and is associated with amino acid characteristics on the capsid surface. Microbiol Spectr. 2023; 11(2): e0380522.

[29] Li X, Ren Y, Chang K, et al. Adipose tissue macrophages as potential targets for obesity and metabolic diseases. Front Immunol. 2023; 14: 1153915.

[30] Kwon Y-W, Chae C-W, Lee H, et al. A subset of macrophages and monocytes in the mouse bone marrow express atypical chemokine receptor 1. Cell Stem Cell. 2022; 29(7): 1016-1017.

[31] Szukiewicz D. CX3CL1 (fractalkine)-CX3CR1 Axis in inflammation-induced angiogenesis and tumorigenesis. Int J Mol Sci. 2024; 25(9): 4679.

[32] Rivas-Fuentes S, Salgado-Aguayo A, Santos-Mendoza T, Sevilla-Reyes E. The role of the CX3CR1-CX3CL1 Axis in respiratory syncytial virus infection and the triggered immune response. Int J Mol Sci. 2024; 25(18): 9800.

[33] Herrero-Cervera A, Soehnlein O, Kenne E. Neutrophils in chronic inflammatory diseases. Cell Mol Immunol. 2022; 19(2): 177-191.

[34] Dahl R, Walsh JC, Lancki D, et al. Regulation of macrophage and neutrophil cell fates by the PU.1:C/EBP ratio and granulocyte colony-stimulating factor. Nat Immunol. 2003; 4(10): 1029-1036.

[35] Liu Q, Yu J, Wang L, et al. Inhibition of PU.1 ameliorates metabolic dysfunction and non-alcoholic steatohepatitis. J Hepatol. 2020; 73(2): 361-370.

[36] Liu M-K, Tang J-J, Li H, et al. Artemisitene ameliorates carbon tetrachloride-induced liver fibrosis by inhibiting NLRP3 inflammasome activation and modulating immune responses. Int Immunopharmacol. 2025; 146: 113818.

[37] Chu C, Wang X, Yang C, et al. Neutrophil extracellular traps drive intestinal microvascular endothelial ferroptosis by impairing Fundc1-dependent mitophagy. Redox Biol. 2023; 67: 102906.

[38] Bhattacharyya S, Oon C, Diaz L, et al. Autotaxin-lysolipid signaling suppresses a CCL11-eosinophil axis to promote pancreatic cancer progression. Nat Can. 2024; 5(2): 283.

[39] Reissing J, Berres M, Strnad P, et al. Th2 cell activation in chronic liver disease is driven by local IL33 and contributes to IL13-dependent fibrogenesis. Cell Mol Gastroenterol Hepatol. 2024; 17(4): 517-538.

[40] Cristina Negrete-Garcia M, Velazquez JR, Popoca-Coyotl A, et al. Chemokine (C-X-C motif) ligand 12/stromal cell-derived Factor-1 is associated with leukocyte recruitment in asthma. Chest. 2010; 138(1): 100-106.

[41] Zhang L, Zhao C, Dai W, et al. Disruption of cholangiocyte-B cell crosstalk by blocking the CXCL12-CXCR4 axis alleviates liver fibrosis. Cell Mol Life Sci. 2023; 80(12): 379.

[42] Aguilar-Bravo B, Arino S, Blaya D, et al. Hepatocyte dedifferentiation profiling in alcohol-related liver disease identifies CXCR4 As A driver of cell reprogramming. J Hepatol.2023; 79(3): 728-740.

[43] Bernard JK, Marakovits C, Smith LG, Francis H. Mast cell and innate immune cell communication in cholestatic liver disease. Semin Liver Dis. 2023; 43(2): 226-233.

[44] Chen J, Feng W, Sun M, et al. TGF-b1-induced SOX18 elevation promotes hepatocellular carcinoma progression and metastasis through transcriptionally upregulating PD-L1 and CXCL12. Gastroenterology. 2024; 167(2): 264-280.

[45] Zhang J-M, Huang H, Li X-Q, et al. FLT3+DC inhibits immune rejection via interaction with Treg in liver transplantation. Int Immunopharmacol. 2024; 137: 112289.

[46] van Montfoort N, van der Aa E, van den Bosch A, et al. Hepatitis B virus surface antigen activates myeloid dendritic cells via a soluble CD14-dependent mechanism. J Virol. 2016; 90(14): 6187-6199.

[47] Cheng D, Chai J, Wang H, Fu L, Peng S, Ni X. Hepatic macrophages: key players in the development and progression of liver fibrosis. Liver Int. 2021; 41(10): 2279-2294.

[48] Varol C, Mildner A, Jung S. Macrophages: development and tissue specialization. Annu Rev Immunol. 2015; 33: 643-675.

[49] David BA, Rezende RM, Antunes MM, et al. Combination of mass cytometry and imaging analysis reveals origin, location, and functional repopulation of liver myeloid cells in mice. Gastroenterology. 2016; 151(6): 1176-1191.

[50] Song G, Liu N. MicroRNA-206 drives antitumor immunity by disrupting the communication between Kupffer cells and Tregs. Cancer Res. 2023; 83(7).

[51] Venzin V, Beccaria C, Fumagalli V, et al. CD4+T cells license Kupffer cells to revert the CD8+T cell dysfunction induced by hepatocellular priming. Eur J Immunol. 2024; 54: 524.

[52] Yu Z, Xie M, Fan X, Jia J. Interferon α2b increases MMP-13 and IL-10 expression in Kupffer cells through MAPK signaling pathways. Hepato-Gastroenterology. 2015; 62(138): 350-354.

[53] Liu J, Yu Q, Wu W, et al. TLR2 stimulation strengthens intrahepatic myeloid-derived cell-mediated T cell tolerance through inducing Kupffer cell expansion and IL-10 production. J Immunol. 2018; 200(7): 2341-2351.

[54] Karakas D, Li J, Ni H. Novel mechanisms of thrombopoietin generation: the essential role of Kupffer cells. Blood. 2021; 138: 3139.

[55] Jiang Y, Tang Y, Hoover C, et al. Kupffer cell receptor CLEC4F is important for the destruction of desialylated platelets in mice. Cell Death Differ. 2021; 28(11): 3009-3021.

[56] Li W, Yang Y, Yang L, Chang N, Li L. Monocyte-derived Kupffer cells dominate in the Kupffer cell pool during liver injury. Cell Rep. 2023; 42(10): 113164.

[57] Peiseler M, David BA, Zindel J, et al. Kupffer cell-like syncytia replenish resident macrophage function in the fibrotic liver. Science. 2023; 381(6662): 1066.

[58] Wan X, Xu C, Yu C, et al. Role of NLRP3 inflammasome in the progression of NAFLD to NASH. Can J Gastroenterol Hepatol. 2016; 2016: 6489012.

[59] Wu X, Dong L, Lin X, Li J. Relevance of the NLRP3 inflammasome in the pathogenesis of chronic liver disease. Front Immunol. 2017; 8: 1728.

[60] Shapouri-Moghaddam A, Mohammadian S, Vazini H, et al. Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol. 2018; 233(9): 6425-6440.

[61] Roh Y-S, Seki E. Chemokines and chemokine receptors in the development of NAFLD. Adv Exp Med Biol. 2018; 1061: 45-53.

[62] Ni Y, Fen Z, Ni L, et al. CX3CL1/CX3CR1 interaction protects against lipotoxicity-induced nonalcoholic steatohepatitis by regulating macrophage migration and M1/M2 status. Metabolism. 2022; 136: 155272.

[63] Dal-Secco D, Wang J, Zeng Z, et al. A dynamic spectrum of monocytes arising from the in situ reprogramming of CCR2⁺ monocytes at a site of sterile injury. J Exp Med. 2015; 212(4): 447-456.

[64] Martin IV, Borkham-Kamphorst E, Zok S, et al. Platelet-derived growth factor (PDGF)-C neutralization reveals differential roles of PDGF receptors in liver and kidney fibrosis. Am J Pathol. 2013; 182(1): 107-117.

[65] Wang BY, Yang H, Fan YY, et al. 3-methyladenine ameliorates liver fibrosis through autophagy regulated by the NF-κB signaling pathways on hepatic stellate cell. Oncotarget. 2017; 8(64): 107603-107611.

[66] Wang Y, Wang J, Zhang J, et al. Stiffness sensing via Piezo1 enhances macrophage efferocytosis and promotes the resolution of liver fibrosis. Sci Adv. 2024; 10(23); eadn3289.

[67] Parthasarathy G, Revelo X, Malhi H. Pathogenesis of nonalcoholic steatohepatitis: An overview. Hepatol Commun. 2020; 4(4): 478-492.

[68] Henderson NC, Rieder F, Wynn TA. Fibrosis: from mechanisms to medicines. Nature. 2020; 587(7835): 555-566.

[69] Xu R, Vujic N, Bianco V, et al. Lipid-associated macrophages between aggravation and alleviation of metabolic diseases. Trends Endocrinol Metab. 2024; 35(11): 981-995.

[70] Ganguly S, Rosenthal SB, Ishizuka K, et al. Lipid- associated macrophages' promotion of fibrosis resolution during MASH regression requires TREM2. Proc Natl Acad Sci USA. 2024; 121(35); e2405746121.

[71] Jaitin DA, Adlung L, Thaiss CA, et al. Lipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner. Cell. 2019; 178(3): 686.

[72] Daemen S, Gainullina A, Kalugotla G, et al. Dynamic shifts in the composition of resident and recruited macrophages influence tissue remodeling in NASH. Cell Rep. 2021; 34(2): 108626.

[73] Guilliams M, Bonnardel J, Haest B, et al. Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches. Cell. 2022; 185(2): 379.

[74] Wang X, He Q, Zhou C, et al. Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development. Immunity. 2023; 56(1): 58.

[75] Li D-P, Huang L, Kan R-R, et al. LILRB2/PirB mediates macrophage recruitment in fibrogenesis of nonalcoholic steatohepatitis. Nat Commun. 2023; 14(1); 4436.

[76] Vegting Y, Jongejan A, Neele AE, et al. Infiltrative classical monocyte-derived and SPP1 lipid-associated macrophages mediate inflammation and fibrosis in ANCA-associated glomerulonephritis. Nephrol Dial Transplant. 2025.

[77] Jiang Y, Yu W, Hu T, et al. Unveiling macrophage diversity in myocardial ischemia-reperfusion injury: identification of a distinct lipid-associated macrophage subset. Front Immunol. 2024; 15: 1335333.

[78] Hou J, Zhang J, Cui P, et al. TREM2 sustains macrophage-hepatocyte metabolic coordination in nonalcoholic fatty liver disease and sepsis. J Clin Invest. 2021; 131(4): e135197.

[79] Zhang Q, Hu C, Feng J, et al. Anti-inflammatory mechanisms of neutrophil membrane-coated nanoparticles without drug loading. J Control Release. 2024; 369: 12-24.

[80] Zhang N, Tang W, Torres L, et al. Cell surface RNAs control neutrophil recruitment. Cell. 2024; 187(4): 846-860.

[81] Mridha AR, Wree A, Robertson AAB, et al. NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. J Hepatol. 2017; 66(5): 1037-1046.

[82] Lai J-L, Liu Y-H, Liu C, et al. Indirubin inhibits LPS-induced inflammation via TLR4 abrogation mediated by the NF-kB and MAPK signaling pathways. Inflammation. 2017; 40(1): 1-12.

[83] Tohme S, Yazdani HO, Al-Khafaji AB, et al. Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress. Cancer Res. 2016; 76(6): 1367-1380.

[84] van der Windt DJ, Sud V, Zhang H, et al. Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis. Hepatology. 2018; 68(4): 1347-1360.

[85] Dokumacioglu E, Iskender H, Kapakin KAT, et al. Effect of betulinic acid administration on TLR-9/NF-κB /IL-18 levels in experimental liver injury. Turk J Med Sci. 2021; 51(3): 1544-1553.

[86] Xia Y, Wang Y, Xiong Q, et al. Neutrophil extracellular traps promote MASH fibrosis by metabolic reprogramming of hepatic stellate cells. Hepatology. 2024; 81(3): 947-961.

[87] Klion AD, Nutman TB. The role of eosinophils in host defense against helminth parasites. J Allergy Clin Immunol. 2004; 113(1): 30-37.

[88] Krishack PA, Hollinger MK, Kuzel TG, et al. IL-33-mediated eosinophilia protects against acute lung injury. Am J Respir Cell Mol Biol. 2021; 64(5): 569-578.

[89] Xu L, Yang Y, Wen Y, et al. Hepatic recruitment of eosinophils and their protective function during acute liver injury. J Hepatol. 2022; 77(2): 344-352.

[90] Yang Y, Xu L, Atkins C, et al. Novel IL-4/HB-EGF-dependent crosstalk between eosinophils and macrophages controls liver regeneration after ischaemia and reperfusion injury. Gut. 2024; 73(9): 1543-1553.

[91] Sumpter TL, Lunz JG, Castellaneta A, et al. Dendritic cell immunobiology in relation to liver transplant outcome. Front Biosci (Elite Ed). 2009; 1(1): 99-114.

[92] Lau AH, Thomson AW. Dendritic cells and immune regulation in the liver. Gut. 2003; 52(2): 307-314.

[93] Thomson AW, Knolle PA. Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol. 2010; 10(11): 753-766.

[94] Ramos MI, Tak PP, Lebre MC. Fms-like tyrosine kinase 3 ligand-dependent dendritic cells in autoimmune inflammation. Autoimmun Rev. 2014; 13(2): 117-124.

[95] Lutz MB, Strobl H, Schuler G, Romani N. GM-CSF monocyte-derived cells and Langerhans cells As part of the dendritic cell family. Front Immunol. 2017; 8: 1388.

[96] Laffont S, Seillet C, Guery J-C. Estrogen receptor-dependent regulation of dendritic cell development and function. Front Immunol. 2017; 8: 108.

[97] Yang H, Kang B, Ha Y, et al. High serum IL-6 correlates with reduced clinical benefit of atezolizumab and bevacizumab in unresectable hepatocellular carcinoma. JHEP Rep. 2023; 5(4): 100672.

[98] Jarido V, Kennedy L, Hargrove L, et al. The emerging role of mast cells in liver disease. Am J Physiol Gastrointest Liver Physiol. 2017; 313(2): G89-G101.

[99] Lombardo J, Broadwater D, Collins R, Cebe K, Brady R, Harrison S. Hepatic mast cell concentration directly correlates to stage of fibrosis in NASH. Hum Pathol. 2019; 86: 129-135.

[100] Gieseck RL, Wilson MS, Wynn TA. Type 2 immunity in tissue repair and fibrosis. Nat Rev Immunol. 2018; 18(1): 62-76.

[101] Min B, Prout M, Hu-Li J, et al. Basophils produce IL-4 and accumulate in tissues after infection with a Th2-inducing parasite. J Exp Med. 2004; 200(4): 507-517.

[102] Jiang X, Wang H. Macrophage subsets at the maternal-fetal interface. Cell Mol Immunol. 2020; 17(8): 889-891.

[103] Vidyarthi A, Agnihotri T, Khan N, et al. Predominance of M2 macrophages in gliomas leads to the suppression of local and systemic immunity. Cancer Immunol Immunother. 2019; 68(12): 1995-2004.

[104] McKell MC, Crowther RR, Schmidt SM, et al. Promotion of anti-tuberculosis macrophage activity by L-arginine in the absence of nitric oxide. Front Immunol. 2021; 12: 653571.

[105] He Y, Wang Y, Jia X, et al. Glycolytic reprogramming controls periodontitis-associated macrophage pyroptosis via AMPK/SIRT1/NF-κB signaling pathway. Int Immunopharmacol. 2023; 119: 110192.

[106] Wang H, Han C, Chen H, et al. Role of HIF-1alpha in hydrogen-induced inhibition of lipopolysaccharide-induced inflammatory responses in mouse macrophages. Chin J Anesthesiol. 2020; 40(7): 881-884.

[107] Mendoza-Reinoso V, Schnepp PM, Baek DY, et al. Bone marrow macrophages induce inflammation by efferocytosis of apoptotic prostate cancer cells via HIF-1α stabilization. Cells. 2022; 11(23): 3712.

[108] Hutami IR, Izawa T, Khurel-Ochir T, Sakamaki T, Iwasa A, Tanaka E. Macrophage motility in wound healing is regulated by HIF-1α via S1P signaling. Int J Mol Sci. 2021; 22(16): 8992.

[109] Yu Q, Guo M, Zeng W, et al. Interactions between NLRP3 inflammasome and glycolysis in macrophages: new insights into chronic inflammation pathogenesis. Immun Inflamm Dis. 2022; 10: e581.

[110] Weng W, Zhang Y, Gui L, et al. PKM2 promotes proinflammatory macrophage activation in ankylosing spondylitis. J Leukoc Biol. 2023; 114(6): 595-603.

[111] Zheng YW, Wang M, Xie JW, et al. Recombinant treponema pallidum protein Tp47 promoted the phagocytosis of macrophages by activating NLRP3 inflammasome induced by PKM2-dependent glycolysis. J Eur Acad Dermatol Venereol. 2023; 37(10): 2067-2079.

[112] Yang W, Tao Y, Wu Y, et al. Neutrophils promote the development of reparative macrophages mediated by ROS to orchestrate liver repair. Nat Commun. 2019; 10(1): 1076.

[113] Liu S, Zhang H, Li Y, et al. S100A4 enhances protumor macrophage polarization by control of PPAR-γ-dependent induction of fatty acid oxidation. J Immunother Cancer. 2021; 9(6): e002548.

[114] Kruglov V, Jang IH, Camell CD. Inflammaging and fatty acid oxidation in monocytes and macrophages. Immunometabolism. 2024; 6(1): e00038.

[115] Qiao S, Lv C, Tao Y, et al. Arctigenin disrupts NLRP3 inflammasome assembly in colonic macrophages via downregulating fatty acid oxidation to prevent colitis-associated cancer. Cancer Lett. 2020; 491: 162-179.

[116] Hohensinner PJ, Lenz M, Haider P, et al. Pharmacological inhibition of fatty acid oxidation reduces atherosclerosis progression by suppression of macrophage NLRP3 inflammasome activation. Biochem Pharmacol. 2021; 190: 114634.

[117] Wang F, Luo L, Wu Z, Wan L, Li F, Wen Z. HMGB1 modulates macrophage metabolism and polarization in ulcerative colitis by inhibiting Cpt1a expression. Front Biosci (Landmark Ed). 2024; 29(11): 387.

[118] Calle P, Munoz A, Sola A, et al. CPT1a gene expression reverses the inflammatory and anti-phagocytic effect of 7-ketocholesterol in RAW264.7 macrophages. Lipids Health Dis. 2019; 18(1): 215.

[119] Lee J-H, Phelan P, Shin M, et al. SREBP-1a-stimulated lipid synthesis is required for macrophage phagocytosis downstream of TLR4-directed mTORC1. Proc Natl Acad Sci USA. 2018; 115(52): E12228-E12234.

[120] Araki M, Nakagawa Y, Saito H, et al. Hepatocyte- or macrophage-specific SREBP-1a deficiency in mice exacerbates methionine- and choline-deficient diet-induced nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol. 2022; 323(6): G627-G639.

[121] Liu S, Yang J, Wu Z. The regulatory role of α-ketoglutarate metabolism in macrophages. Mediat Inflamm. 2021; 2021: 5577577.

[122] Zhang J, Liu X, Wan C, et al. NLRP3 inflammasome mediates M1 macrophage polarization and IL-1β production in inflammatory root resorption. J Clin Periodontol. 2020; 47(4): 451-460.

[123] Hong S, Yu J-W. Prolonged exposure to lipopolysaccharide induces NLRP3-independent maturation and secretion of interleukin (IL)-1β in macrophages. J Microbiol Biotechnol. 2018; 28(1): 115-121.

[124] Wang C, Chen Q, Chen S, et al. Serine synthesis sustains macrophage IL-1β production via NAD⁺-dependent protein acetylation. Mol Cell. 2024; 84(4): 744-759.

[125] Shan X, Hu P, Ni L, et al. Serine metabolism orchestrates macrophage polarization by regulating the IGF1-p38 axis. Cell Mol Immunol. 2022; 19(11): 1263-1278.

[126] 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. Cell Stem Cell. 2023; 30(3): 283.

[127] Carbonaro M, Wang K, Huang H, et al. IL-6-GP130 signaling protects human hepatocytes against lipid droplet accumulation in humanized liver models. Sci Adv. 2023; 9(15): eadf4490.

[128] Wen Y, Feng D, Wu H, et al. Defective initiation of liver regeneration in Osteopontin-deficient mice after partial hepatectomy due to insufficient activation of IL-6/Stat3 pathway. Int J Biol Sci. 2015; 11(10): 1236-1247.

[129] Averilla J, Li Z, Zhao J, et al. Kupffer cells undergo anti-inflammatory adaptive changes in the early phase of alcohol exposure. Hepatology. 2020; 72: 175A.

[130] Xia T, Zhang M, Lei W, et al. Advances in the role of STAT3 in macrophage polarization. Front Immunol. 2023; 14: 1160719.

[131] Wu B-M, Liu J-D, Li Y-H, Li J. Margatoxin mitigates CCl4-induced hepatic fibrosis in mice via macrophage polarization, cytokine secretion and STAT signaling. Int J Mol Med. 2020; 45(1): 103-114.

[132] Zhang F, Wang H, Wang X, et al. TGF-β induces M2-like macrophage polarization via SNAIL-mediated suppression of a pro-inflammatory phenotype. Oncotarget. 2016; 7(32): 52294-52306.

[133] Kawakubo A, Miyagi M, Yokozeki Y, et al. Origin of M2 Mφ and its macrophage polarization by TGF-β in a mice intervertebral injury model. Int J Immunopathol Pharmacol. 2022; 36: 03946320221103792.

[134] Fan W, Qu Y, Yuan X, Shi H, Liu G. Loureirin B accelerates diabetic wound healing by promoting TGFβ/Smad-dependent macrophage M2 polarization: A concerted analytical approach through single-cell RNA sequencing and experimental verification. Phytother Res. 2024.

[135] Wang J, Wu Z, Huang Y, et al. IRF4 induces M1 macrophage polarization and aggravates ulcerative colitis progression by the Bcl6-dependent STAT3 pathway. Environ Toxicol. 2024; 39(4): 2390-2404.

[136] Miao J, Yong Y, Zheng Z, et al. Artesunate inhibits neointimal hyperplasia by promoting IRF4 associated macrophage polarization. Adv Sci. 2025; 12: e2408992.

[137] Roeszer T. What is an M2 macrophage? Historical overview of the macrophage polarization model. The Th1/Th2 and M1/M2 paradigm, the arginine fork. M2 Macrophage. Vol 86 Springer; 2020: 3-25.

[138] Seidman JS, Troutman TD, Sakai M, et al. Niche-specific reprogramming of epigenetic landscapes drives myeloid cell diversity in nonalcoholic steatohepatitis. Immunity. 2020; 52(6): 1057.

[139] Zhu Y, Shang L, Tang Y, et al. Genome-wide profiling of H3K27ac identifies TDO2 as a pivotal therapeutic target in metabolic associated steatohepatitis liver disease. Adv Sci. 2024; 11(45): e2404224.

[140] Wu J, Gong L, Li Y, et al. SGK1 aggravates idiopathic pulmonary fibrosis by triggering H3k27ac-mediated macrophage reprogramming and disturbing immune homeostasis. Int J Biol Sci. 2024; 20(3): 968-986.

[141] Fang J-Z, Li C, Liu X-Y, Hu TT, Fan ZS, Han ZG. Hepatocyte-specific Arid1a deficiency initiates mouse steatohepatitis and hepatocellular carcinoma. PLoS One. 2015; 10(11): e0143042.

[142] Li B, Huo Y, Lin Z, et al. DNA hydroxymethylase 10-11 translocation 2 (TET2) inhibits mouse macrophage activation and polarization. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2017; 33(9): 1165-1170.

[143] Fan W, Liu P, Tan L, et al. Tet2 modulates M2 macrophage polarization via mRNA 5-methylcytosine in allergic rhinitis. Int Immunopharmacol. 2024; 143: 113495.

[144] Ross JB, Myers LM, Noh JJ, et al. Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity. Nature. 2024; 628(8006): 162.

[145] Drechsler M, Soehnlein O. The complexity of arterial classical monocyte recruitment. J Innate Immun. 2013; 5(4): 358-366.

[146] Tacke F. Cenicriviroc for the treatment of non-alcoholic steatohepatitis and liver fibrosis. Expert Opin Investig Drugs. 2018; 27(3): 301-311.

[147] Soto MPD, Lim JK. Evaluating the therapeutic potential of Cenicriviroc in the treatment of nonalcoholic steatohepatitis with fibrosis: A brief report on emerging data. Hepat Med. 2020; 12: 115-123.

[148] Theyab A, Algahtani M, Alsharif KF, et al. New insight into the mechanism of granulocyte colony-stimulating factor (G-CSF) that induces the mobilization of neutrophils. Hematology. 2021; 26(1): 628-636.

[149] Mouchemore KA, Anderson RL, Hamilton JA. Neutrophils, G-CSF and their contribution to breast cancer metastasis. FEBS J. 2018; 285(4): 665-679.

[150] Ding W, Zhou D, Zhang S, Qian J, Yang L, Tang L. Trimetazidine inhibits liver fibrosis and hepatic stellate cell proliferation and blocks transforming growth factor-β (TGFβ)/Smad signaling in vitro and in vivo. Bioengineered. 2022; 13(3): 7147-7156.

[151] Xiang-An Z, Guangmei C, Yong L, et al. Curcumin reduces Ly6Chi monocyte infiltration to protect against liver fibrosis by inhibiting Kupffer cells activation to reduce chemokines secretion. Biomed Pharmacother. 2018; 106: 868-878.

[152] Zhang S, Sun W-Y, Wu J-J, et al. Targeting the TGF-β signaling pathway in liver diseases. Chinese Pharmacol Bull. 2013; 29(11): 1489-1493.

[153] Reiter FP, Wimmer R, Wottke L, et al. Role of interleukin-1 and its antagonism of hepatic stellate cell proliferation and liver fibrosis in the Abcb4(−/−) mouse model. World J Hepatol. 2016; 8(8): 401-410.

[154] Huang Y-H, Chen M-H, Guo Q-L, Chen ZX, Chen QD, Wang XZ. Interleukin-10 induces senescence of activated hepatic stellate cells via STAT3-p53 pathway to attenuate liver fibrosis. Cell Signal. 2020; 66: 109445.

[155] Chou WY, Lu CN, Lee TH, et al. Electroporative interleukin-10 gene transfer ameliorates carbon tetrachlo-ride-induced murine liver fibrosis by MMP and TIMP modulation. Acta Pharmacol Sin. 2006; 27(4): 469-476.

[156] Mahamid M, Paz K, Reuven M, Safadi R. Hepatotoxicity due to tocilizumab and anakinra in rheumatoid arthritis: two case reports. Int J Gen Med. 2011; 4: 657-660.

[157] Mahamid M, Mader R, Safadi R. Hepatotoxicity of tocilizumab and anakinra in rheumatoid arthritis: management decisions. Clin Pharm. 2011; 3: 39-43.

[158] Zhou GP, Jiang YZ, Sun LY, Zhu ZJ. Therapeutic effect and safety of stem cell therapy for chronic liver disease: a systematic review and meta-analysis of randomized controlled trials. Stem Cell Res Ther. 2020; 11(1): 419.

[159] Liu P, Mao Y, Xie Y, Wei J, Yao J. Stem cells for treatment of liver fibrosis/cirrhosis: clinical progress and therapeutic potential. Stem Cell Res Ther. 2022; 13(1): 356.

[160] Meivar-Levy I, Zoabi F, Nardini G, et al. The role of the vasculature niche on insulin-producing cells generated by transdifferentiation of adult human liver cells. Stem Cell Res Ther. 2019; 10: 53.

[161] Rostami T, Kasaeian A, Maleki N, et al. The effect of bone marrow-derived mesenchymal stem cell co-transplantation with hematopoietic stem cells on liver fibrosis alleviation and survival in patients with class III β-thalassemia major. Stem Cell Res Ther. 2021; 12(1): 213.

[162] Yao YQ, Xia ZM, Cheng FY, et al. Human placental mesenchymal stem cells ameliorate liver fibrosis in mice by upregulation of Caveolin1 in hepatic stellate cells. Stem Cell Res Ther. 2021; 12(1): 294.

[163] Wang Y, Zhang W, Zhang C, van HQT, Seino T, Zhang Y. Reducing functionally defective old HSCs alleviates aging-related phenotypes in old recipient mice. Cell Res. 2025; 35(1): 45-58.

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