Tehran University of Medical Sciences International Journal of Hematology-Oncology and Stem Cell Research 2008-2207 20 1 2026 02 09 46 58 Mahdi Alaee Shahid Rajaee Hospital, Qazvin University of Medical Sciences, Qazvin, Iran Meysam Moulaee Department of Biochemistry, Faculty of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran Kimia Taebi 1) Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran 2)USERN Office, Qazvin University of Medical Sciences, Qazvin, Iran Ahoura Haghi Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Italy Maryam Hormozi Department of Biochemistry, Faculty of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran Mehdi Azad Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Qazvin University of Medical Sciences, Qazvin, Iran 2025 01 23 2025 12 01 Hepatocellular carcinoma (HCC) is a crucial health concern worldwide, representing a leading cause of cancer-related mortality and the most common form of primary liver cancer. The aggressive nature of HCC is mainly due to its high intention for invasion and metastasis, processes that are regulated by a complex network of genetic and molecular pathways. Among the critical regulators of these processes is microRNA-21 (miR-21), a small non-coding RNA that has been implicated in various oncogenic activities. This review provides a comprehensive analysis of the role of miR-21 in promoting HCC metastasis progression, with a particular focus on its interaction with key signaling pathways, including the PTEN/PI3K/AKT, PDCD4/AP-1, RECK/MMP, and TIMP-3 axes. By targeting tumor suppressors, miR-21 facilitates epithelial-to-mesenchymal transition (EMT), invasion, and metastasis of HCC cells. Understanding the molecular mechanisms regulated by miR-21 not only sheds light on the pathogenesis of HCC but also highlights possible therapeutic targets for combating this aggressive cancer. https://ijhoscr.tums.ac.ir/index.php/ijhoscr/article/view/2388 https://ijhoscr.tums.ac.ir/index.php/ijhoscr/article/download/2388/1119