Exploring the Molecular and Immune Mechanisms Linking Hypothyroidism to Hepatocellular Carcinoma

² Department of Thoracic Surgery II, Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, China,

³ Department of Radiotherapy V, Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, China,

⁴ Department of General Surgery II, Guangdong Provincial Second Traditional Chinese Medicine Hospital, Guangdong, China.,

PAR 2025 , 9(5), 28–41; https://doi.org/10.26689/par.v9i5.12016

© 2025 by the Authors. Licensee Whioce Publishing, Singapore. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )

Abstract

Background: Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors worldwide, and endocrine, metabolic, and immune factors influence its occurrence and progression. Hypothyroidism (HT) is a common endocrine disorder that may affect cancer risk; however, its relationship with HCC remains unclear. Objective: This study aimed to investigate the potential molecular and immune mechanisms underlying the association between HT and HCC, with a focus on the regulatory effects of HT-related genetic variants on the hepatic tumor immune microenvironment. Methods: Single-nucleotide polymorphisms (SNPs) associated with HT and HCC identified through Mendelian randomization were functionally annotated using the Ensembl Genome Browser and mapped to candidate genes. Functional enrichment and pathway analyses were performed with Metascape. Differentially expressed target genes between HCC and normal liver tissues were screened using GEPIA2, and their protein expression levels were validated in the Human Protein Atlas (HPA) database. The association between target gene expression and immune cell infiltration was further evaluated using TIMER2.0. Results: A total of 68 candidate genes were analyzed. Enrichment analysis revealed that these genes are involved in IFN-γ–mediated immune responses, PI3K/AKT and RAC1 signaling pathways, and other immune regulatory processes. Among them, HLA-DQA1, HLA-DPB1, HLA-DQA2, and PVT1 showed significant differential expression in HCC. HLA-DQA1, HLA-DPB1, and HLA-DQA2 were positively correlated with CD8⁺ T cells, regulatory T cells (Tregs), and M2 macrophages, suggesting that these genes may exert bidirectional effects on antitumor immunity and immunosuppression. PVT1 may influence the immune microenvironment by regulating myeloid cell recruitment and extracellular matrix remodeling. Conclusion: HLA-DQA1, HLA-DPB1, HLA-DQA2, and PVT1 may reduce the risk of HCC by enhancing IFN-γ–mediated antitumor immunity and modulating key signaling pathways, while also contributing to immune microenvironment remodeling. These findings provide mechanistic insights into the protective effects of HT on HCC and suggest potential targets for immunotherapeutic strategies.

References

Oh J, Jun D, 2023, The Latest Global Burden of Liver Cancer: A Past and Present Threat. Clinical and Molecular Hepatology, 29(2): 355–357.

Zhang C, Liu S, Yang M, 2021, Hepatocellular Carcinoma and Obesity, Type 2 Diabetes Mellitus, Cardiovascular Disease: Causing Factors, Molecular Links, and Treatment Options. Frontiers in Endocrinology, 12: 808526.

Hu X, Chen Y, Shen Y, et al., 2022, Global Prevalence and Epidemiological Trends of Hashimoto’s Thyroiditis in Adults: A Systematic Review and Meta-Analysis. Frontiers in Public Health, 10: 1020709.

Krashin E, Piekiełko-Witkowska A, Ellis M, et al., 2019, Thyroid Hormones and Cancer: A Comprehensive Review of Preclinical and Clinical Studies. Frontiers in Endocrinology, 10: 59.

Thvilum M, Brandt F, Almind D, et al., 2013, Type and Extent of Somatic Morbidity Before and After the Diagnosis of Hypothyroidism: A Nationwide Register Study. PLoS One, 8(9): e75789.

Yang R, Li J, Zhang H, et al., 2025, Exploring the Molecular Mechanisms of Comorbidity Between Thyroid Cancer and Breast Cancer Through Multi-Omics Data. Scientific Reports, 15(1): 23309.

Wang B, Lu Z, Huang Y, et al., 2020, Does Hypothyroidism Increase the Risk of Breast Cancer: Evidence From a Meta-Analysis. BMC Cancer, 20(1): 733.

Davies N, Holmes M, Davey S, 2018, Reading Mendelian Randomisation Studies: A Guide, Glossary, and Checklist for Clinicians. BMJ (Clinical Research Ed.), 362: k601.

Lu L, Wan B, Li L, et al., 2022, Hypothyroidism Has a Protective Causal Association With Hepatocellular Carcinoma: A Two-Sample Mendelian Randomization Study. Frontiers in Endocrinology, 13: 987401.

Hunt S, Moore B, Amode R, et al., 2022, Annotating and Prioritizing Genomic Variants Using the Ensembl Variant Effect Predictor–A Tutorial. Human Mutation, 43(8): 986–997.

Meng X, Pan B, Zhang Z, et al., 2023, Functional Pathway and Process Enrichment Analysis of Genes Associated With Morphological Abnormalities of the Outer Ear. The Journal of Craniofacial Surgery, 34(2): 489–493.

Tang Z, Kang B, Li C, et al., 2019, GEPIA2: An Enhanced Web Server for Large-Scale Expression Profiling and Interactive Analysis. Nucleic Acids Research, 47(W1): W556–W560.

Zhou Y, Zhou B, Pache L, et al., 2019, Metascape Provides a Biologist-Oriented Resource for the Analysis of Systems-Level Datasets. Nature Communications, 10(1): 1523.

Li T, Fu J, Zeng Z, et al., 2020, TIMER2.0 for Analysis of Tumor-Infiltrating Immune Cells. Nucleic Acids Research, 48(W1): W509–W514.

Jorgovanovic D, Song M, Wang L, et al., 2020, Roles of IFN-γ in Tumor Progression and Regression: A Review. Biomarker Research, 8: 49.

Verga F, Petrucci E, Patriarca V, et al., 2007, Thyroid Hormone Receptor TRβ1 Mediates Akt Activation by T3 in Pancreatic Beta Cells. Journal of Molecular Endocrinology, 38(1–2): 221–233.

Ishina I, Zakharova M, Kurbatskaia I, et al., 2023, MHC Class II Presentation in Autoimmunity. Cells, 12(2): 314.

Seliger B, Kloor M, Ferrone S, 2017, HLA Class II Antigen-Processing Pathway in Tumors: Molecular Defects and Clinical Relevance. Oncoimmunology, 6(2): e1171447.

Li R, Wang X, Zhu C, et al., 2022, lncRNA PVT1: A Novel Oncogene in Multiple Cancers. Cellular & Molecular Biology Letters, 27(1): 84.

He G, Bao N, Wang S, et al., 2021, Ketamine Induces Ferroptosis of Liver Cancer Cells by Targeting lncRNA PVT1/miR-214-3p/GPX4. Drug Design, Development and Therapy, 15: 3965–3978.

Guo J, Hao C, Wang C, et al., 2018, Long Noncoding RNA PVT1 Modulates Hepatocellular Carcinoma Cell Proliferation and Apoptosis by Recruiting EZH2. Cancer Cell International, 18: 98.

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