CCDC77 and SLC45A3 mediate the genetic mechanism of Hashimoto's thyroiditis through IL-6

Hashimoto's thyroiditis (HT) is a common autoimmune thyroid disorder with a complex genetic background. Interleukin-6 (IL-6) has been implicated in its pathogenesis, but the genetic mechanisms remain unclear. Two-sample Mendelian randomization (MR) using expression quantitative trait loci (eQTL) and gene set enrichment analysis (GWAS) data identified IL‑6–HT genes. In vivo validation in nonobese diabetic (NOD) mice involved siRNA knockdown, histopathology HE/Immunohistochemistry (HE/IHC), and enzyme-linked immunosorbent assay (ELISA). GSEA and molecular docking explored mechanisms. Western blot in THP‑1 cells assessed Nuclear factor kappa-light-chain-enhancer of activated B cells (NF‑κB) pathway proteins (pIKKβ, IKKβ, pTAK1, TAK1, pp65, p65) and associations with SLC45A3/CCDC77 at 2, 24, 48 h (β‑actin control). MR analysis identified CCDC77 and SLC45A3 as key genes associated with both IL-6 and HT. In vivo experiments showed that knockdown of CCDC77 exacerbated thyroid damage, increased serum anti-thyroperoxidase antibody (TPOAb), anti-thyroglobulin antibody (TGAb), and IL-6 levels, while reduced free triiodothyronine (FT3) and free thyroxine (FT4). Conversely, SLC45A3 knockdown alleviated thyroiditis, reduced antibody levels, and improved thyroid function. GSEA Western blot analysis further revealed that both CCDC77 and SLC45A3 were involved in regulating the activation of NF‑κB signaling pathway. Our study demonstrated that SLC45A3 and CCDC77 were involved in modulating HT progression through NF‑κB-IL-6 axis, providing novel therapeutic strategies for clinical applications.