Revealing the Protective Role of the TSC1-BRD2-Ferroptosis Axis in Papillary Thyroid Carcinoma: A Multi-Stage Genetic and Functional Integrative Analysis Study

Introduction : Papillary thyroid carcinoma (PTC) represents the most prevalent thyroid malignancy, with some cases exhibiting aggressive features and treatment resistance. Ferroptosis, an iron-dependent form of programmed cell death, remains poorly understood in PTC. The aim of this study was to explore ferroptosis-related mechanisms and identify key regulatory networks and potential therapeutic targets in PTC. Methods : A multi-stage integrative analysis strategy was employed, combining Mendelian randomization (MR), mediation analysis, and bioinformatics validation. Ferroptosis-related proteins associated with PTC risk were screened using protein quantitative trait loci (pQTL) data from the deCODE database and PTC genome-wide association study (GWAS) data from FinnGen. Upstream regulatory molecules were identified using pQTL data from the UK Biobank, and a molecular regulatory axis was constructed through mediation analysis. Differential expression and co-expression analyses were conducted using TCGA and GTEx databases to validate functional relevance. Results : The study revealed the TSC1-BRD2-ferroptosis axis, where TSC1 regulated BRD2 expression to suppress the ferroptosis pathway. This regulatory axis demonstrated significant differential expression and co-expression relationships in PTC tissues, supporting its functional relevance. Conclusion : This study established, for the first time, the protective role of the TSC1-BRD2-ferroptosis axis in PTC, providing new insights into the pathogenesis of the disease.