Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 24 6 2025 10 29 718 733 Sahar Rahimi Department of Physiology and Pharmacology, Physiology Research Center, Kerman University of Medical Sciences, Kerman, Iran Ali Derakhshani Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, Kerman, Iran Atena Alifarsangi Department of Physiology and Pharmacology, Physiology Research Center, Kerman University of Medical Sciences, Kerman, Iran Mohammad Hosein Shakeri Goki Anesthesia Department, School of Allied Medical Sciences, Education Development Center (EDC), Rafsanjan University of Medical Sciences, Rafsanjan, Iran. Seyedeh Mahdieh Khoshnazar Gastroenterology and Hepatology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran Nader Shahrokhi Department of Physiology and Pharmacology, Physiology Research Center, Kerman University of Medical Sciences, Kerman, Iran 2025 05 30 2025 08 31 Liver fibrosis is known as a condition characterized by chronic inflammation and excessive extracellular matrix deposition that causes cirrhosis and liver failure. Stem cell therapy is a promising strategy for the management of liver fibrosis because it not only improves tissue regeneration but also modulates by immunomodulatory mechanisms. This systematic review aimed to evaluate the immunoregulatory effects of stem cells in both experimental models and clinical studies of liver fibrosis. A total of 29 studies were included, comprising several stem cell sources, including bone marrow-derived mesenchymal stem cells (BM-MSCs), umbilical cord-derived MSCs (UC-MSCs), adipose tissue-derived MSCs (AT-MSCs), and stem cells from human exfoliated deciduous teeth (SHED), among others. Studies reported that stem cells could decrease proinflammatory cytokines (e.g., TNF-α, IFN-γ, IL-17) and fibrosis-related markers, while increasing levels of anti-inflammatory cytokines (e.g., IL-10, IL-4) and regulatory immune cells such as Tregs (regulatory T cells). Stem cells could affect immune homeostasis via modulating in macrophage polarization, T cell subsets, and B cell activity, resulting in attenuated fibrotic progression and improved liver function. Despite variability in cell types, routes of administration, and fibrosis models, the results support the potential of stem cell therapy to reform the hepatic immune microenvironment. However, more standardized protocols and clinical validations are required. This study emphasizes the immunomodulatory potential of stem cells as a therapeutic method in liver fibrosis. It brings a clear view into their mechanisms of action and the foundation for future translational applications.  https://ijaai.tums.ac.ir/index.php/ijaai/article/view/4471 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/4471/2238