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It highlights key pathways in HSC modulation, including TGF-β, PDGF, Wnt/β-catenin, and NF-κB. Therapeutic prospects include immunomodulatory strategies, macrophage polarization, NK-based therapies, and stem cell-derived exosomes, plus combination regimens and immune profiling while addressing immune heterogeneity in chronic liver 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responses.",{"name":74,"@type":61,"acceptedAnswer":75},"What therapeutic strategies are proposed to prevent or reverse fibrosis?",{"text":76,"@type":64},"Potential approaches include immunomodulatory agents, strategies influencing macrophage polarization and NK-cell-based therapies, stem cell-derived exosomes, and combination therapies integrating immunotherapies with anti-fibrotic agents, supported by immune profiling while considering immune heterogeneity.","https://schema.org",{"og:url":32,"og:type":79,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":81,"canonical":32},"index,follow",{"doc_id":83,"site_id":7},420953,1790918253,{"code":4,"msg":86,"data":87},"success",[88,92,96,100,105,110,114,119,124,127,131],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Story & 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[https://doi.org/10.1155/jimr/2656395](https://doi.org/10.1155/jimr/2656395)  \nReview Article  \nImmune System and Hepatic Stellate Cells’ Crosstalk in Liver Fibrosis: Pathways and Therapeutic Potential  \nWahyu Widowati ,1 Adilah Hafizha Nur Sabrina,2 Annisa Firdaus Sutendi ,2 Fadhilah Haifa Zahiroh ,2 Aris Muhamad Nurjamil ,2 Teresa Liliana Wargasetia ,1 Ita MargarethaNainggolan ,3 Rizal Azis ,4 Elham Rismani ,5 and Massoud Vosough 6,7,8  \n1Faculty of Medicine, Maranatha Christian University, Bandung, West Java 40164, Indonesia  \n2Aretha Medika Utama, Biomolecular and Biomedical Research Center, Bandung 40163, West Java, Indonesia  \n3School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Jakarta 14440, Indonesia  \n4Biomedical Engineering, Department of Electrical Engineering, Faculty of Engineering, University of Indonesia, Depok, Indonesia 5Molecular Medicine Department, Biotechnology Research Center (BRC), Pasteur Institute of Iran, Tehran, Iran  \n6Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Tehran, Iran  \n7Experimental Cancer Medicine, Institution for Laboratory Medicine, and Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden  \n8Department of Cellular and Molecular Biology, Faculty of Sciences and Advanced Technology in Biology,  \nUniversity of Science and Culture, Tehran, Iran  \nCorrespondence should be addressed to Wahyu Widowati; [wahyu_w60@yahoo.com](wahyu_w60@yahoo.com), Elham Rismani; [el.rismani@gmail.com](el.rismani@gmail.com), and  \nMassoud Vosough; [massoud.vosough@gmail.com](massoud.vosough@gmail.com)  \nReceived 1 September 2025; Revised 19 November 2025; Accepted 10 December 2025  \nAcademic Editor: Poorani Gurumallesh Prabu  \nCopyright © 2026 Wahyu Widowati et al. Journal of Immunology Research published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.  \nLiver fibrosis, characterized by the excessive deposition of extracellular matrix (ECM) driven by hepatic stellate cells (HSCs) activation, remains a critical challenge due to its progression to cirrhosis and hepatocellular carcinoma (HCC) . This review clarifies the complex crosstalk between the immune system and HSCs, highlighting key cellular players including macrophages, natural killer (NK) cells, regulatory T cells (Tregs), and their cytokine-mediated signaling pathways that regulate fibrogenesis and fibrosis resolution. We describe pivotal molecular mechanisms such as transforming growth factor (TGF)-β, platelet-derived growth factor (PDGF), Wnt/β-catenin, and NF-κB signaling in HSCs modulation, emphasizing their interplay with immune responses. Novel therapeutic strategies targeting this complex immune–HSCs interaction, ranging from immunomodulatory agents, macrophage polarization, and NK cell-based therapies, to stem cell-derived exosomes, offer promising opportunities for preventing and reversing fibrosis. We further discuss innovative combination therapies integrating immunotherapies with antifibrotic agents, personalized strategies based on immune profiling, and the challenges of immune heterogeneity in fibrosis management. This review discusses recent advances in molecular interplay of immune system and HSCs, highlighting novel therapeutic targets, and future perspectives for managing chronic liver diseases.  \nKeywords: extracellular matrix (ECM); hepatic stellate cells (HSCs); immune system; liver fibrosis; therapeutic strategies  \n1. Introduction  \nLiver fibrosis is defined as the excessive deposition of extracellular matrix (ECM) components in the liver, resulting from chronic liver injury and inflammation. This pathological  \nprocess is characterized by the modulation of hepatic","cbCairv92NsCsg1W","https://ap.wps.com/l/cbCairv92NsCsg1W","pdf",937429,16,"English","# Introduction\n## Pathophysiology and etiologies of liver fibrosis\n## Immune activation, ECM-driven progression, and reversibility\n## Limitations of current therapies and need for immune-targeted approaches","[{\"question\":\"How do hepatic stellate cells contribute to liver fibrosis?\",\"answer\":\"Hepatic stellate cell (HSC) activation leads to excessive deposition of extracellular matrix (ECM) components, including collagen, in response to hepatocyte damage and inflammatory stimuli.\"},{\"question\":\"Which immune cell types and signals are emphasized in the immune–HSC crosstalk?\",\"answer\":\"The review highlights macrophages, natural killer (NK) cells, and regulatory T cells (Tregs), focusing on cytokine-mediated signaling pathways that regulate fibrogenesis and fibrosis resolution.\"},{\"question\":\"What molecular pathways within HSCs are discussed as key regulators?\",\"answer\":\"Major pathways include transforming growth factor (TGF)-β, platelet-derived growth factor (PDGF), Wnt/β-catenin, and NF-κB signaling, with emphasis on their interplay with immune responses.\"},{\"question\":\"What therapeutic strategies are proposed to prevent or reverse fibrosis?\",\"answer\":\"Potential approaches include immunomodulatory agents, strategies influencing macrophage polarization and NK-cell-based therapies, stem cell-derived exosomes, and combination therapies integrating immunotherapies with anti-fibrotic agents, supported by immune profiling while considering immune heterogeneity.\"}]","Immune System and Hepatic Stellate Cells’ Crosstalk in Liver Fibrosis - Pathways and Therapeutic Potential | PDF",1790623263]