Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 23 6 2024 12 29 699 726 Atieh Pourbagheri-Sigaroodi Pediatric Infections Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran Majid Momeny Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran Nima Rezaei Research Center for Immunodeficiencies, Children's Medical Center Hospital, Tehran University of Medical Sciences, Tehran, Iran AND Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran AND Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Fatemeh Fallah Pediatric Infections Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran Davood Bashash Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran 2024 04 22 2024 06 24 Despite therapeutic advancements, treatment failure in hepatocellular carcinoma (HCC) continues to pose a significant obstacle. Given the vital role of the tumor immune microenvironment (TIM) in HCC and the promising effectiveness of immune therapies, we aimed to elucidate potential predictive biomarkers by developing a prognostic model based on immune-related genes (IRGs). After obtaining data, differentially expressed IRGs were identified, and prognostic models were developed using Cox regression analyses. Key contributors of the model were identified and the results were validated by experimental assays in HCC cell lines. Our eight-IRG signature can serve as an independent prognostic factor in HCC. The low-risk group exhibited superior overall survival and lower tumor mutation burden (TMB). The high-risk group showed elevated proportions of immune cells, including regulatory T cells and resting CD4+ memory T cells. We found that the NEAT1-C1/miR-542-5p/BIRC5 regulatory network may serve as a potential target in HCC. The experimental investigations showed that BIRC5 inhibition reduced the metabolic activity in four HCC cell lines. The results of this study facilitate patient stratification and the development of more effective treatment strategies, particularly for high-risk HCC patients. https://ijaai.tums.ac.ir/index.php/ijaai/article/view/4088 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/4088/2126