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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\u2010mediated signaling pathways that regulate fibrogenesis and fibrosis resolution. We describe pivotal molecular mechanisms such as transforming growth factor (TGF)\u2010\u03b2, platelet\u2010derived growth factor (PDGF), Wnt\/\u03b2\u2010catenin, and NF\u2010\u03baB signaling in HSCs modulation, emphasizing their interplay with immune responses. Novel therapeutic strategies targeting this complex immune\u2013HSCs interaction, ranging from immunomodulatory agents, macrophage polarization, and NK cell\u2010based therapies, to stem cell\u2010derived 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.<\/jats:p>","DOI":"10.1155\/jimr\/2656395","type":"journal-article","created":{"date-parts":[[2026,1,3]],"date-time":"2026-01-03T06:00:28Z","timestamp":1767420028000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Immune System and Hepatic Stellate Cells\u2019 Crosstalk in Liver Fibrosis: Pathways and Therapeutic Potential"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5401-7794","authenticated-orcid":false,"given":"Wahyu","family":"Widowati","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5872-9228","authenticated-orcid":false,"given":"Adilah Hafizha 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