CCDC77 exacerbates, SLC45A3 alleviates Hashimoto's thyroiditis via NF-κB-IL-6 axis

Hashimoto's thyroiditis (HT) is a prevalent autoimmune thyroid disorder characterized by chronic inflammation and metabolic alterations, for which current treatments primarily focus on hormone replacement. While oral levothyroxine sodium tablets effectively normalize thyroid function, they do not address the underlying autoimmune pathology or reduce concentrations of thyroid-related autoantibodies. Interleukin-6 (IL-6) has been implicated in HT pathogenesis, but the precise genetic mechanisms linking IL-6 to disease progression remain largely unclear. Understanding these genetic drivers could unlock novel therapeutic targets beyond symptomatic management.

Researchers employed two-sample Mendelian randomization (MR) using expression quantitative trait loci (eQTL) and genome-wide association study (GWAS) data to identify IL-6-associated HT genes. In vivo validation was conducted in nonobese diabetic (NOD) mice involving siRNA knockdown of target genes. Histopathology (HE/IHC) and enzyme-linked immunosorbent assay (ELISA) were used to assess thyroid damage and immune markers. Gene set enrichment analysis (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 their associations with SLC45A3 and CCDC77 at 2, 24, 48 h using β-actin as a control.

Mendelian randomization analysis identified CCDC77 and SLC45A3 as key genes significantly associated with both IL-6 levels and Hashimoto's thyroiditis. In vivo experiments in NOD mice demonstrated distinct roles for these genes: knockdown of CCDC77 exacerbated thyroid damage, leading to increased serum anti-thyroperoxidase antibody (TPOAb), anti-thyroglobulin antibody (TGAb), and IL-6 levels, while simultaneously reducing free triiodothyronine (FT3) and free thyroxine (FT4). Conversely, knockdown of SLC45A3 significantly alleviated thyroiditis, resulting in reduced antibody levels and improved thyroid function. Further GSEA and Western blot analysis in THP-1 cells revealed that both CCDC77 and SLC45A3 were critically involved in regulating the activation of the NF-κB signaling pathway. This indicates a direct mechanistic link.

The study demonstrated that SLC45A3 and CCDC77 modulate HT progression through the NF-κB-IL-6 axis, providing novel genetic targets for therapeutic intervention.