OBJECTIVE To investigate the effects and mechanisms of Yanghe Decoction (YHD) in ameliorating cognitive dysfunction associated with experimental autoimmune thyroiditis (EAT) in rats through modulation of the thyroid-brain axis.

METHODS EAT was induced in female Sprague-Dawley rats by repeated immunization with porcine thyroglobulin and Freund’s adjuvant, while 0.5% Lugol’s iodine was supplied in drinking water. Following successful model establishment, rats received low-dose (5 g·kg⁻¹) or high-dose (15 g·kg⁻¹) YHD by gavage for 6 weeks. Serum TPOAb and TgAb were measured by ELISA. Hippocampal IL-1β, IL-6, TNF-α, and COX-2 levels were quantified. Thyroid histopathology was assessed by hematoxylin-eosin (HE) staining, and cognitive function was evaluated with the Morris water maze. Network pharmacology, molecular docking, and untargeted LC-MS/MS metabolomics were used to identify the bioactive components of YHD and the pathways through which it ameliorates EAT-related cognitive impairment. Hippocampal protein expression of epidermal growth factor receptor (EGFR), caspase-3 (CASP3), tumor necrosis factor (TNF), synapsin-1, postsynaptic density protein-95 (PSD-95), and glutamate ionotropic receptor AMPA type subunit 1 (GluA1) was measured by Western blot.

RESULTS YHD reduced thyroid lymphocytic infiltration and lowered serum TPOAb and TgAb levels in a dose-dependent manner. In the Morris water maze, YHD shortened escape latency and increased platform crossings and target-quadrant dwell time, indicating improved cognitive performance. Network pharmacology showed that intersecting targets were enriched in EGFR and insulin signaling pathways. Further molecular docking experiments demonstrated strong binding affinities between β-sitosterol and EGFR, β-sitosterol and CASP3, quercetin and EGFR, quercetin and TNF, and kaempferol and TNF. Hippocampal metabolomics further revealed that YHD downregulated arachidonic acid, linoleic acid, and palmitic acid, restored docosahexaenoic acid, and corrected polyunsaturated fatty acid dysregulation. Mechanistically, compared with the model group, both low and high doses of YHD significantly reduced the expression levels of hippocampal COX-2 and its effector prostaglandin E₂, inhibited the expression of IL-1β, IL-6, and TNF-α, and downregulated the protein levels of TNF, EGFR, and CASP3; ultimately, the treatment restored hippocampal protein expression of Synapsin-1, PSD-95, and GluA1, thereby maintaining synaptic function.

CONCLUSION YHD alleviates cognitive dysfunction in EAT rats, likely by reducing thyroid autoantibodies, correcting polyunsaturated fatty acid metabolic disturbances, suppressing hippocampal inflammation, and restoring synaptic plasticity. These findings provide network pharmacology, metabolomic, and molecular evidence that YHD acts through the thyroid–brain axis to mitigate AIT-associated cognitive impairment.