<p>Epilepsy, a complex neurological condition, might intertwine with various immune system anomalies, including autoimmune hyperthyroidism. An overactive thyroid gland due to immune system misdirection could subtly influence epilepsy via mechanisms not fully understood. Our investigation leverages Mendelian randomization (MR) to dissect this association, aiming to illuminate the role of serum metabolites as a possible bridge connecting these conditions. A comprehensive MR analysis was conducted in three phases, using genetic variants from GWAS datasets. The first phase assessed the causal effect of autoimmune hyperthyroidism on epilepsy. The second phase examined the impact of 1400 serum metabolites on epilepsy. The final phase explored the mediation of these metabolites in the autoimmune hyperthyroidism-epilepsy pathway. The analysis employed inverse variance weighted (IVW) methods, along with sensitivity analyses including MR-Egger and weighted median approaches, to ensure robustness. Our Mendelian randomization analysis identifies a significant causal relationship from autoimmune hyperthyroidism to epilepsy. We observed that genetic predisposition towards autoimmune hyperthyroidism is associated with reduced risk of developing epilepsy (<i>P</i> = 0.037). Sensitivity analyses, such as culling analysis and funnel plot inspections, confirm the consistency and robustness of this finding. Further analysis revealed cAMP as a mediator in this causal pathway (<i>P</i> = 0.016), underscoring its role in the link between autoimmune hyperthyroidism and epilepsy. Conversely, no causal effect of epilepsy on the development of autoimmune hyperthyroidism was found, highlighting a unidirectional relationship. This study proposes that autoimmune hyperthyroidism may act as a protective factor against epilepsy, with this effect potentially mediated by serum metabolites, particularly cAMP. These findings provide novel insights into the interplay between autoimmune conditions, metabolic alterations, and neurological disorders, highlighting cAMP as a promising therapeutic target of epilepsy.</p> Graphical Abstract <p>This graphical abstract illustrates the potential protective mechanism of autoimmune hyperthyroidism against epilepsy through the modulation of serum adenosine 3′,5′-cyclic monophosphate (cAMP) levels. Elevated thyroid hormone levels in autoimmune hyperthyroidism may enhance adenylate cyclase activity, increasing the conversion of ATP to cAMP, while simultaneously affecting phosphodiesterase function, reducing cAMP breakdown and leading to its accumulation. The increased cAMP levels may upregulate the GABAergic pathway, thereby dampening neuronal excitability and lowering the likelihood of seizures. Our study, leveraging a Mendelian randomization approach, provides evidence that autoimmune hyperthyroidism is associated with a decreased risk of epilepsy, a finding supported by extensive sensitivity analyses, including MR-Egger regression. Further investigation into the specific mechanisms, including the role of CREB and its impact on ion channels and neurotransmitter systems, is necessary to fully understand the complex interplay between autoimmune disorders and neurological diseases, and to establish novel therapeutic strategies for epilepsy management. Illustrations created at BioRender.com</p> <p></p>