Exploring the Molecular and Immune Mechanisms Linking Hypothyroidism to Hepatocellular Carcinoma

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.