Hepatic Stellate Cells Interact with the Immune System: A Bidirectional Crosstalk Network Driving Liver Fibrosis

Abstract

As a central metabolic and immune organ, the liver maintains a unique immune microenvironment which is crucial for sustaining health. When the immune balance in the liver is disrupted, it can drive the occurrence and progression of various chronic liver diseases, including liver fibrosis. Hepatic stellate cells (HSCs) are the key effector cells responsible for producing extracellular matrix (ECM) during liver fibrosis, and the hepatic immune microenvironment precisely regulates their activation. This review focuses on the complex bidirectional interaction network between HSCs and major immune cells in the liver, including macrophages, natural killer (NK) cells, and T cells. It systematically elucidates the central role of these interactions in maintaining hepatic homeostasis, mediating inflammatory responses, and driving the progression of fibrosis. A deeper understanding of the interaction between HSCs and immune cells is essential for elucidating the pathological mechanisms of liver fibrosis and will provide a theoretical basis for developing innovative therapeutic strategies targeting the immune microenvironment.

Keywords

HSC / Macrophages / NK cells / Immune interactions / Liver fibrosis

Author Contributions

Conceptualization, C.-N.Z., G.-Y.S. and H.-J.L. Methodology, C.-N.Z., G.-Y.S. and H.-J.L.; Investigation, C.-N.Z., G.-Y.S. and H.W.; Data Curation, C.-N.Z., Y.-X.Z. and Z.-C.G.; Writing—Original Draft, C.-N.Z.; Writing—Review & Editing, H.-J.L., G.-Y.S., H.W. and Y.-X.Z.; Visualization, Z.-C.G. and Y.-X.Z.; Supervision, H.-J.L.; Project Administration, H.-J.L.; Funding Acquisition, H.-J.L.

Ethics Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All data used in the present study are available from the corresponding author upon reasonable request.

Funding

This research was funded by the Natural Science Foundation of Jilin Province (YDZJ202401218ZYTS to HL).

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

[1] Tarantino G, Citro V, Balsano C. Liver-spleen axis in nonalcoholic fatty liver disease. Expert Rev. Gastroenterol. Hepatol. 2021, 15, 759-769. DOI:10.1080/17474124.2021.1914587

[2] Gilgenkrantz H, Sayegh RA, Lotersztajn S. Immunoregulation of Liver Fibrosis: New Opportunities for Antifibrotic Therapy. Annu. Rev. Pharmacol. Toxicol. 2025, 65, 281-299. DOI:10.1146/annurev-pharmtox-020524-012013

[3] Novobrantseva TI, Majeau GR, Amatucci A, Kogan S, Brenner I, Casola S, et al. Attenuated liver fibrosis in the absence of B cells. J. Clin. Investig. 2005, 115, 3072-3082. DOI:10.1172/JCI24798

[4] Shen J, Huang S, Wang Y, Wang Q, Lin S, Guan W, et al. PAD4⁺ neutrophils promote hepatic stellate cell activation and accelerate MASH fibrosis progression viaNET-DNA/TAOK1/MAPK pathways. JCI Insight 2026, 11, e191479. DOI:10.1172/jci.insight.191479

[5] Mathä L, Romera-Hernández M, Steer CA, Yin YH, Orangi M, Shim H, et al. Migration of Lung Resident Group 2 Innate Lymphoid Cells Link Allergic Lung Inflammation and Liver Immunity. Front. Immunol. 2021, 12, 679509. DOI:10.3389/fimmu.2021.679509

[6] Kisseleva T, Brenner D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat. Rev. Gastroenterol. Hepatol. 2021, 18, 151-166. DOI:10.1038/s41575-020-00372-7

[7] Ma X, Qiu J, Zou S, Tan L, Miao T. The role of macrophages in liver fibrosis: Composition, heterogeneity, and therapeutic strategies. Front. Immunol. 2024, 15, 1494250. DOI:10.3389/fimmu.2024.1494250

[8] Ouyang R, Li X, Hao J, Lin J, Lan H, Peng J, et al. Decoding the heterogeneity of liver-resident macrophages in chronic liver diseases: Therapeutic responses to immunomodulatory strategies. Front. Pharmacol. 2025, 16, 1708240. DOI:10.3389/fphar.2025.1708240

[9] Wen Y, Lambrecht J, Ju C, Tacke F. Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities. Cell Mol. Immunol. 2021, 18, 45-56. DOI:10.1038/s41423-020-00558-8

[10] Li W, Chen L, Zhou Q, Huang T, Zheng W, Luo F, et al. Liver macrophage-derived exosomal miRNA-342-3p promotes liver fibrosis by inhibiting HPCAL1 in stellate cells. Hum. Genom. 2025, 19, 9. DOI:10.1186/s40246-025-00722-z

[11] Zhong H, Liu C, Huang Z, Tan P, Chen H, Fu W. Crosstalk between Hepatic Stellate Cells and Hepatic Macrophages in Metabolic Dysfunction-Associated Steatohepatitis. Am. J. Pathol. 2025, 195, 1040-1056. DOI:10.1016/j.ajpath.2025.02.003

[12] Ran J, Yin S, Issa R, Zhao Q, Zhu G, Zhang H, et al. Key role of macrophages in the progression of hepatic fibrosis. Hepatol. Commun. 2025, 9, e0602. DOI:10.1097/HC9.0000000000000602

[13] Yin X, Liu M, Xu Y, Zhong H, Zhang J, Xie H, et al. Macrophage-derived DLL4 promotes liver fibrosis by activating the Notch pathway in hepatic stellate cells. Free Radic. Biol. Med. 2026, 242, 431-443. DOI:10.1016/j.freeradbiomed.2025.10.275

[14] Feng D, Guan Y, Wang Y, Maccioni L, Mackowiak B, Gao B. Characterisation of macrophages in healthy and diseased livers in mice: Identification of necrotic lesion-associated macrophages. eGastroenterology 2025, 3, e100189. DOI:10.1136/egastro-2025-100189

[15] Li J, Zhao YR, Tian Z. Roles of hepatic stellate cells in acute liver failure: From the perspective of inflammation and fibrosis. World J. Hepatol. 2019, 11, 412-420. DOI:10.4254/wjh.v11.i5.412

[16] Seki E, De Minicis S, Österreicher CH, Kluwe J, Osawa Y, Brenner DA, et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat. Med. 2007, 13, 1324-1332. DOI:10.1038/nm1663

[17] Li Z, Ying W, Zhuang T, Xie Y, Kim J. Exercise-mediated macrophage polarization modulates the targeted therapeutic effect of NAFLD: A review. Phys. Act. Nutr. 2023, 27, 10-16. DOI:10.20463/pan.2023.0023

[18] Zou X, Ke Y, Shao Y, Liu S, Shi T. Liver Fibrosis: Interactions Between Cells and Microenvironments. Turk. J. Gastroenterol. 2025, 36, 711-722. DOI:10.5152/tjg.2025.25313

[19] Campbell JS, Hughes SD, Gilbertson DG, Palmer TE, Holdren MS, Haran AC, et al. Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. Proc. Natl. Acad. Sci. USA 2005, 102, 3389-3394. DOI:10.1073/pnas.0409722102

[20] Kocabayoglu P, Lade A, Lee YA, Dragomir AC, Sun X, Fiel MI, et al. β-PDGF receptor expressed by hepatic stellate cells regulates fibrosis in murine liver injury, but not carcinogenesis. J. Hepatol. 2015, 63, 141-147. DOI:10.1016/j.jhep.2015.01.036

[21] Han H, Yu D, Liu Y, Jia H, Liu W. Matrix mechanical remodeled carrier-free nanosystem for programmable closed-loop reversal of liver fibrosis via STING alkylation. Sci. Adv. 2025, 11, eadz4126. DOI:10.1126/sciadv.adz4126

[22] Sun L, Wang Y, Kan T, Wang H, Cui J, Wang L, et al. Elevated expression of Piezo1 activates the cGAS-STING pathway in chondrocytes by releasing mitochondrial DNA. Osteoarthr. Cartil. 2025, 33, 601-615. DOI:10.1016/j.joca.2025.02.778

[23] Wang X, Rao H, Zhao J, Wee A, Li X, Fei R, et al. STING expression in monocyte-derived macrophages is associated with the progression of liver inflammation and fibrosis in patients with nonalcoholic fatty liver disease. Lab. Investig. 2020, 100, 542-552. DOI:10.1038/s41374-019-0342-6

[24] Kim DM, Pan Q, Liu Z, Ai W, Han HW, Banu SK, et al. GHSR-Foxo1 Signaling in Macrophages Promotes Liver Fibrosis via Inflammatory Response and Hepatic Stellate Cell Activation. Adv. Sci. 2025, 12, e04223. DOI:10.1002/advs.202504223

[25] Zheng Q, Cao Y, Jiang X, Wang X, Wang X, He Y, et al. Decoding the CHI3L1/IL-13Rα2 signaling nexus in MASH-fibrosis pathogenesis. Sci. Adv. 2025, 11, eadz3223. DOI:10.1126/sciadv.adz3223

[26] Li X, Liu S, Li T, Yang Q, Chen Y, Meng Y, et al. Inflammatory factor CCL2 enhances the interaction between monocyte-macrophage cells and liver parenchymal cells to promote liver inflammation and fibrosis in biliary atresia. BMC Pediatr. 2025, 25, 643. DOI:10.1186/s12887-025-05984-z

[27] Guo S, Zhang Q, Guo Y, Yin X, Zhang P, Mao T, et al. The role and therapeutic targeting of the CCL2/CCR2 signaling axis in inflammatory and fibrotic diseases. Front. Immunol. 2024, 15, 1497026. DOI:10.3389/fimmu.2024.1497026

[28] 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, 2279-2294. DOI:10.1111/liv.14940

[29] Geervliet E, Karkdijk E, Bansal R. Inhibition of intrahepatic monocyte recruitment by Cenicriviroc and extracellular matrix degradation by MMP1 synergistically attenuate liver inflammation and fibrogenesis in vivo. Sci. Rep. 2024, 14, 16897. DOI:10.1038/s41598-024-67926-6

[30] Xi S, Zheng X, Li X, Jiang Y, Wu Y, Gong J, et al. Activated Hepatic Stellate Cells Induce Infiltration and Formation of CD163⁺ Macrophages via CCL2/CCR2 Pathway. Front. Med. 2021, 8, 627927. DOI:10.3389/fmed.2021.627927

[31] Baeck C, Wei X, Bartneck M, Fech V, Heymann F, Gassler N, et al. Pharmacological inhibition of the chemokine C-C motif chemokine ligand 2 (monocyte chemoattractant protein 1) accelerates liver fibrosis regression by suppressing Ly-6C (⁺) macrophage infiltration in mice. Hepatology 2014, 59, 1060-1072. DOI:10.1002/hep.26783

[32] Yagura K, Ohtaki H, Tsumuraya T, Sato A, Miyamoto K, Kawada N, et al. The enhancement of CCL2 and CCL5 by human bone marrow-derived mesenchymal stem/stromal cells might contribute to inflammatory suppression and axonal extension after spinal cord injury. PLoS ONE 2020, 15, e0230080. DOI:10.1371/journal.pone.0230080

[33] Meran S, Martin J, Luo DD, Steadman R, Phillips A. Interleukin-1β induces hyaluronan and CD44-dependent cell protrusions that facilitate fibroblast-monocyte binding. Am. J. Pathol. 2013, 182, 2223-2240. DOI:10.1016/j.ajpath.2013.02.038

[34] Sipka T, Peroceschi R, Hassan-Abdi R, Groß M, Ellett F, Begon-Pescia C, et al. Damage-Induced Calcium Signaling and Reactive Oxygen Species Mediate Macrophage Activation in Zebrafish. Front. Immunol. 2021, 12, 636585. DOI:10.3389/fimmu.2021.636585

[35] Li W, Luo F, Wu X, Fan B, Yang M, Zhong W, et al. Anti-Inflammatory Effects and Mechanisms of Dandelion in RAW264.7 Macrophages and Zebrafish Larvae. Front. Pharmacol. 2022, 13, 906927. DOI:10.3389/fphar.2022.906927

[36] Través PG, Luque A, Hortelano S. Macrophages, inflammation, and tumor suppressors: ARF, a new player in the game. Mediat. Inflamm. 2012, 2012, 568783. DOI:10.1155/2012/568783

[37] Li B, Dong B, Xie L, Li Y. Exploring Advances in Natural Plant Molecules for Allergic Rhinitis Immunomodulation In Vivo and In Vitro. Int. J. Gen. Med. 2025, 18, 529-565. DOI:10.2147/IJGM.S493021

[38] Ge Z, Chen Y, Ma L, Hu F, Xie L. Macrophage polarization and its impact on idiopathic pulmonary fibrosis. Front. Immunol. 2024, 15, 1444964. DOI:10.3389/fimmu.2024.1444964

[39] Weng SY, Wang X, Vijayan S, Tang Y, Kim YO, Padberg K, et al. IL-4 Receptor Alpha Signaling through Macrophages Differentially Regulates Liver Fibrosis Progression and Reversal. EBioMedicine 2018, 29, 92-103. DOI:10.1016/j.ebiom.2018.01.028

[40] Wang L, Yang K, Xie X, Wang S, Gan H, Wang X, et al. Macrophages as Multifaceted Orchestrators of Tissue Repair: Bridging Inflammation, Regeneration, and Therapeutic Innovation. J. Inflamm. Res. 2025, 18, 8945-8959. DOI:10.2147/JIR.S527764

[41] Friedman SL. Mac the knife? Macrophages- the double-edged sword of hepatic fibrosis. J. Clin. Investig. 2005, 115, 29-32. DOI:10.1172/JCI23928

[42] Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S, et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Investig. 2005, 115, 56-65. DOI:10.1172/JCI22675

[43] Yu S, Ji G, Zhang L. The role of p 53 in liver fibrosis. Front. Pharmacol. 2022, 13, 1057829. DOI:10.3389/fphar.2022.1057829

[44] Xiao Y, Wu ZN, Lu J, Wang YD. Role of metabolic reprogramming-mediated hepatic stellate cell activation in the pathogenesis of hepatic fibrosis. Zhonghua Gan Zang Bing Za Zhi 2024, 32, 1053-1056. DOI:10.3760/cma.j.cn501113-20240223-00088

[45] Lagente V, Le Quement C, Boichot E. Macrophage metalloelastase (MMP-12) as a target for inflammatory respiratory diseases. Expert. Opin. Ther. Targets 2009, 13, 287-295. DOI:10.1517/14728220902751632

[46] Zhang S, Wan D, Zhu M, Wang G, Zhang X, Huang N, et al. CD11b⁺ CD43^hi Ly6C^lo splenocyte-derived macrophages exacerbate liver fibrosis via spleen-liver axis. Hepatology 2023, 77, 1612-1629. DOI:10.1002/hep.32782

[47] Sun Y, Zhao M, Cheng L, He X, Shen S, Lv J, et al. Reduction of alternative polarization of macrophages by short-term activated hepatic stellate cell-derived small extracellular vesicles. J. Exp. Clin. Cancer Res. 2025, 44, 117. DOI:10.1186/s13046-025-03380-0

[48] Shi H, Wang X, Sloas C, Gerlach B, Yurdagul A, Moore MP, et al. Impaired TIM4-mediated efferocytosis by liver macrophages contributes to fibrosis in metabolic dysfunction-associated steatohepatitis. Sci. Transl. Med. 2025, 17, eadv2106. DOI:10.1126/scitranslmed.adv2106

[49] Seyfried AN, Maloney JM, MacNamara KC. Macrophages Orchestrate Hematopoietic Programs and Regulate HSC Function During Inflammatory Stress. Front. Immunol. 2020, 11, 1499. DOI:10.3389/fimmu.2020.01499

[50] Huang X, Li Z, Huang Y, Zhang Q, Cui Y, Shi X, et al. Vimentin intermediate filaments coordinate actin stress fibers and podosomes to determine the extracellular matrix degradation by macrophages. Dev. Cell 2025, 60, 1669-1685.e6. DOI:10.1016/j.devcel.2025.01.016

[51] Zheng M, Tian Z. Liver-Mediated Adaptive Immune Tolerance. Front. Immunol. 2019, 10, 2525. DOI:10.3389/fimmu.2019.02525

[52] Zhang Y, Wu Y, Shen W, Wang B, Yuan X. Crosstalk between NK cells and hepatic stellate cells in liver fibrosis (Review). Mol. Med. Rep. 2022, 25, 208. DOI:10.3892/mmr.2022.12724

[53] Fink T, Ebbesen P, Koppelhus U, Zachar V. Natural killer cell-mediated basal and interferon-enhanced cytotoxicity against liver cancer cells is significantly impaired under in vivo oxygen conditions. Scand. J. Immunol. 2003, 58, 607-612. DOI:10.1111/j.1365-3083.2003.01347.x

[54] Kahraman A, Fingas CD, Syn WK, Gerken G, Canbay A. Role of stress-induced NKG2D ligands in liver diseases. Liver Int. 2012, 32, 370-382. DOI:10.1111/j.1478-3231.2011.02608.x

[55] Muhanna N, Tair LA, Doron S, Amer J, Azzeh M, Mahamid M, et al. Amelioration of hepatic fibrosis by NK cell activation. Gut 2011, 60, 90-98. DOI:10.1136/gut.2010.211136

[56] Tao X, Zhang R, Du R, Yu T, Yang H, Li J, et al. EP3 enhances adhesion and cytotoxicity of NK cells toward hepatic stellate cells in a murine liver fibrosis model. J. Exp. Med. 2022, 219, e20212414. DOI:10.1084/jem.20212414

[57] Gao B, Radaeva S. Natural killer and natural killer T cells in liver fibrosis. Biochim. Biophys. Acta 2013, 1832, 1061-1069. DOI:10.1016/j.bbadis.2012.09.008

[58] Zhang Q, Bi J, Zheng X, Chen Y, Wang H, Wu W, et al. Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat. Immunol. 2018, 19, 723-732. DOI:10.1038/s41590-018-0132-0

[59] Choi W, Ryu T, Lee J, Shim Y, Kim M, Kim H, et al. Metabotropic Glutamate Receptor 5 in Natural Killer Cells Attenuates Liver Fibrosis by Exerting Cytotoxicity to Activated Stellate Cells. Hepatology 2021, 74, 2170-2185. DOI:10.1002/hep.31875

[60] Jeong WI, Park O, Suh YG, Byun JS, Park SY, Choi E, et al. Suppression of innate immunity (natural killer cell/interferon-γ) in the advanced stages of liver fibrosis in mice. Hepatology 2011, 53, 1342-1351. DOI:10.1002/hep.24190

[61] Zheng M, Sun H, Tian Z. Natural killer cells in liver diseases. Front. Med. 2018, 12, 269-279. DOI:10.1007/s11684-018-0621-4

[62] Gergues M, Bari R, Koppisetti S, Gosiewska A, Kang L, Hariri RJ. Senescence, NK cells, and cancer: Navigating the crossroads of aging and disease. Front. Immunol. 2025, 16, 1565278. DOI:10.3389/fimmu.2025.1565278

[63] Cadoux M, Caruso S, Pham S, Gougelet A, Pophillat C, Riou R, et al. Expression of NKG2D ligands is downregulated by β-catenin signalling and associates with HCC aggressiveness. J. Hepatol. 2021, 74, 1386-1397. DOI:10.1016/j.jhep.2021.01.017

[64] Gur C, Doron S, Kfir-Erenfeld S, Horwitz E, Abu-tair L, Safadi R, et al. NKp46-mediated killing of human and mouse hepatic stellate cells attenuates liver fibrosis. Gut 2012, 61, 885-893. DOI:10.1136/gutjnl-2011-301400

[65] Gong Y, Jin L, Duan L, Xiao J, Li Y, Wang H, et al. Extracellular Vesicles Derived From Streptococcus anginosus Aggravate Lupus Nephritis by Triggering TLR2-MyD88-NF-κB Signalling in NK Cells. J. Extracell. Vesicles 2025, 14, e70134. DOI:10.1002/jev2.70134

[66] Rodriguez-Sevilla JJ, Ganan-Gomez I, Kumar B, Thongon N, Ma F, Chien KS, et al. Natural killer cells’ functional impairment drives the immune escape of pre-malignant clones in early-stage myelodysplastic syndromes. Nat. Commun. 2025, 16, 3450. DOI:10.1038/s41467-025-58662-0

[67] Li R, Li Z, Feng Y, Yang H, Shi Q, Tao Z, et al. PDGFRβ-targeted TRAIL specifically induces apoptosis of activated hepatic stellate cells and ameliorates liver fibrosis. Apoptosis 2020, 25, 105-119. DOI:10.1007/s10495-019-01583-3

[68] Jang JH, Kim H, Jun H, Park CY, Kim JY, Yeo M, et al. Targeting RBM39 with Tasisulam enhances TRAIL-induced apoptosis through DR5 upregulation and Bcl-2 downregulation in renal cell carcinoma. Biochem. Pharmacol. 2025, 236, 116877. DOI:10.1016/j.bcp.2025.116877

[69] Gao B, Radaeva S, Jeong WI. Activation of natural killer cells inhibits liver fibrosis: A novel strategy to treat liver fibrosis. Expert Rev. Gastroenterol. Hepatol. 2007, 1, 173-180. DOI:10.1586/17474124.1.1.173

[70] Correia AL, Guimaraes JC, Auf der Maur P, De Silva D, Trefny MP, Okamoto R, et al. Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy. Nature 2021, 594, 566-571. DOI:10.1038/s41586-021-03614-z

[71] Huang Y, Chen M, Guo Q, Chen Y, Zhang L, Chen Z, et al. Interleukin-10 promotes primary rat hepatic stellate cell senescence by upregulating the expression levels of p53 and p21. Mol. Med. Rep. 2018, 17, 5700-5707. DOI:10.3892/mmr.2018.8592

[72] Gao Y, Chi Y, Chen Y, Wang W, Li H, Zheng W, et al. Multi-omics analysis of human mesenchymal stem cells shows cell aging that alters immunomodulatory activity through the downregulation of PD-L1. Nat. Commun. 2023, 14, 4373. DOI:10.1038/s41467-023-39958-5

[73] Jin H, Jia Y, Yao Z, Huang J, Hao M, Yao S, et al. Hepatic stellate cell interferes with NK cell regulation of fibrogenesis via curcumin induced senescence of hepatic stellate cell. Cell. Signal. 2017, 33, 79-85. DOI:10.1016/j.cellsig.2017.02.006

[74] Wang L, Wang Y, Quan J. Exosomes derived from natural killer cells inhibit hepatic stellate cell activation and liver fibrosis. Hum. Cell 2020, 33, 582-589. DOI:10.1007/s13577-020-00371-5

[75] Wang L, Wang Y, Quan J. Exosomal miR-223 derived from natural killer cells inhibits hepatic stellate cell activation by suppressing autophagy. Mol. Med. 2020, 26, 81. DOI:10.1186/s10020-020-00207-w

[76] Li QY, Gong T, Huang YK, Kang L, Warner CA, Xie H, et al. Role of noncoding RNAs in liver fibrosis. World J. Gastroenterol. 2023, 29, 1446-1459. DOI:10.3748/wjg.v29.i9.1446

[77] Market M, Tennakoon G, Scaffidi M, Cook DP, Angka L, Ng J, et al. Preventing Surgery-Induced NK Cell Dysfunction Using Anti-TGF-β Immunotherapeutics. Int. J. Mol. Sci. 2022, 23, 14608. DOI:10.3390/ijms232314608

[78] Huang Y, Chen Z, Jang JH, Baig MS, Bertolet G, Schroeder C, et al. PD-1 blocks lytic granule polarization with concomitant impairment of integrin outside-in signaling in the natural killer cell immunological synapse. J. Allergy Clin. Immunol. 2018, 142, 1311-1321.e8. DOI:10.1016/j.jaci.2018.02.050

[79] Fugier E, Marche H, Thélu MA, Macek Jílková Z, Van Campenhout N, Dufeu-Duchesne T, et al. Functions of liver natural killer cells are dependent on the severity of liver inflammation and fibrosis in chronic hepatitis C. PLoS ONE 2014, 9, e95614. DOI:10.1371/journal.pone.0095614

[80] Wang X, Lin R, Li D, Ye W, Yang Z, Wu N, et al. Modulation of γδ T cells by USF3: Implications for liver fibrosis and immune regulation. Int. Immunopharmacol. 2025, 148, 114100. DOI:10.1016/j.intimp.2025.114100

[81] Cardon A, Guinebretière T, Dong C, Gil L, Ado S, Gavlovsky PJ, et al. Single cell profiling of circulating autoreactive CD4 T cells from patients with autoimmune liver diseases suggests tissue imprinting. Nat. Commun. 2025, 16, 1161. DOI:10.1038/s41467-025-56363-2

[82] Martin OP, Wallace MS, Oetheimer C, Patel HB, Butler MD, Wong LP, et al. Single-cell atlas of human liver and blood immune cells across fatty liver disease stages reveals distinct signatures linked to liver dysfunction and fibrogenesis. Nat. Immunol. 2025, 26, 1596-1611. DOI:10.1038/s41590-025-02255-y

[83] Burtis AEC, DeNicola DMC, Ferguson ME, Santos RG, Pinilla C, Kriss MS, et al. Ag-driven CD8⁺ T cell clonal expansion is a prominent feature of MASH in humans and mice. Hepatology 2025, 81, 591-608. DOI:10.1097/HEP.0000000000000971

[84] Zhan C, Peng C, Wei H, Wei K, Ou Y, Zhang Z. Diverse Subsets of γδT Cells and Their Specific Functions Across Liver Diseases. Int. J. Mol. Sci. 2025, 26, 2778. DOI:10.3390/ijms26062778

[85] Zhou QH, Wu FT, Pang LT, Zhang TB, Chen Z. Role of γδT cells in liver diseases and its relationship with intestinal microbiota. World J. Gastroenterol. 2020, 26, 2559-2569. DOI:10.3748/wjg.v26.i20.2559

[86] Chamroonkul N, Bansal MB. HIV and the liver. Nat. Rev. Gastroenterol. Hepatol. 2019, 16, 1-2. DOI:10.1038/s41575-018-0085-7

[87] Garcia-Broncano P, Medrano LM, Berenguer J, González-García J, Jiménez-Sousa MÁ, Carrero A, et al. Dysregulation of the Immune System in HIV/HCV-Coinfected Patients According to Liver Stiffness Status. Cells 2018, 7, 196. DOI:10.3390/cells7110196

[88] Kim AY, Chung RT. Coinfection with HIV-1 and HCV—A one-two punch. Gastroenterology 2009, 137, 795-814. DOI:10.1053/j.gastro.2009.06.040

[89] Basset L, Chevalier S, Danger Y, Arshad MI, Piquet-Pellorce C, Gascan H, et al. Interleukin-27 and IFNγ regulate the expression of CXCL9, CXCL10, and CXCL11 in hepatitis. J. Mol. Med. 2015, 93, 1355-1367. DOI:10.1007/s00109-015-1319-6

[90] Ji J, Chen Z, He W, Chen Y, Ye D, Zhong Y, et al. CXCR6 defines a distinct resident state in γδ T cells for protecting from liver cirrhosis. Hepatology 2025, 10-1097. DOI:10.1097/HEP.0000000000001643

[91] Knight B, Akhurst B, Matthews VB, Ruddell RG, Ramm GA, Abraham LJ, et al. Attenuated liver progenitor (oval) cell and fibrogenic responses to the choline deficient, ethionine supplemented diet in the BALB/c inbred strain of mice. J. Hepatol. 2007, 46, 134-141. DOI:10.1016/j.jhep.2006.08.015

[92] Hadian Y, Bagood MD, Dahle SE, Sood A, Isseroff RR. Interleukin-17: Potential Target for Chronic Wounds. Mediat. Inflamm. 2019, 2019, 1297675. DOI:10.1155/2019/1297675

[93] Kong X, Feng D, Wang H, Hong F, Bertola A, Wang FS, et al. Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice. Hepatology 2012, 56, 1150-1159. DOI:10.1002/hep.25744

[94] Yoon JS, Lee CW. Protein phosphatases regulate the liver microenvironment in the development of hepatocellular carcinoma. Exp. Mol. Med. 2022, 54, 1799-1813. DOI:10.1038/s12276-022-00883-0

[95] Seki E, Schwabe RF. Hepatic inflammation and fibrosis: Functional links and key pathways. Hepatology 2015, 61, 1066-1079. DOI:10.1002/hep.27332

[96] Roh YS, Park S, Lim CW, Kim B. Depletion of Foxp3⁺ Regulatory T Cells Promotes Profibrogenic Milieu of Cholestasis-Induced Liver Injury. Dig. Dis. Sci. 2015, 60, 2009-2018. DOI:10.1007/s10620-014-3438-2

[97] Li J, Qiu SJ, She WM, Wang FP, Gao H, Li L, et al. Significance of the balance between regulatory T (Treg) and T helper 17 (Th17) cells during hepatitis B virus related liver fibrosis. PLoS ONE 2012, 7, e39307. DOI:10.1371/journal.pone.0039307

[98] Wu KJ, Qian QF, Zhou JR, Sun DL, Duan YF, Zhu X, et al. Regulatory T cells (Tregs) in liver fibrosis. Cell Death Discov. 2023, 9, 53. DOI:10.1038/s41420-023-01347-8

[99] Savage TM, Fortson KT, de los Santos-Alexis K, Oliveras-Alsina A, Rouanne M, Rae SS, et al. Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis. Immunity 2024, 57, 303-318.e6. DOI:10.1016/j.immuni.2024.01.009

[100] Ajith A, Merimi M, Arki MK, Hossein-khannazer N, Najar M, Vosough M, et al. Immune regulation and therapeutic application of T regulatory cells in liver diseases. Front. Immunol. 2024, 15, 1371089. DOI:10.3389/fimmu.2024.1371089

[101] Koda Y, Teratani T, Chu PS, Hagihara Y, Mikami Y, Harada Y, et al. CD8⁺ tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells. Nat. Commun. 2021, 12, 4474. DOI:10.1038/s41467-021-24734-0

[102] Wang W, Green M, Choi JE, Gijón M, Kennedy PD, Johnson JK, et al. CD8⁺ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 2019, 569, 270-274. DOI:10.1038/s41586-019-1170-y

[103] Wang H, Tsung A, Mishra L, Huang H. Regulatory T cell: A double-edged sword from metabolic-dysfunction-associated steatohepatitis to hepatocellular carcinoma. eBioMedicine 2024, 101, 105031. DOI:10.1016/j.ebiom.2024.105031

[104] Winau F, Quack C, Darmoise A, Kaufmann SHE. Starring stellate cells in liver immunology. Curr. Opin. Immunol. 2008, 20, 68-74. DOI:10.1016/j.coi.2007.10.006

[105] Zhao W, Su W, Kuang P, Zhang L, Liu J, Yin Z, et al. The role of hepatic stellate cells in the regulation of T-cell function and the promotion of hepatocellular carcinoma. Int. J. Oncol. 2012, 41, 457-464. DOI:10.3892/ijo.2012.1497

[106] Li X, Su Y, Hua X, Xie C, Liu J, Huang Y, et al. Levels of hepatic Th17 cells and regulatory T cells upregulated by hepatic stellate cells in advanced HBV-related liver fibrosis. J. Transl. Med. 2017, 15, 75. DOI:10.1186/s12967-017-1167-y

[107] Aoyama T, Inokuchi S, Brenner DA, Seki E. CX3CL1-CX3CR1 interaction prevents carbon tetrachloride-induced liver inflammation and fibrosis in mice. Hepatology 2010, 52, 1390-1400. DOI:10.1002/hep.23795

[108] Tao J, Wu Z, Liang Y, Wang J, Tang M, Huang S, et al. Lhx2 specifically expressed in HSCs promotes liver regeneration and inhibits liver fibrosis. Hepatology 2025, 82, 683-701. DOI:10.1097/HEP.0000000000001201

[109] Ma F, Liu X, Zhang Y, Tao Y, Zhao L, Abusalamah H, et al. Tumor extracellular vesicle-derived PD-L1 promotes T cell senescence through lipid metabolism reprogramming. Sci. Transl. Med. 2025, 17, eadm7269. DOI:10.1126/scitranslmed.adm7269