J. Xu, L. Huo, J. Liu, W. Xu and T. Yu (2026). Ketogenic diet can inhibit epileptic seizures by inhibiting RGMa methylation to promote GluA1 palmitoylation in the epileptic rat model. Nutrition & metabolism, 23(1), 30. https://doi.org/10.1186/s12986-026-01090-8

PubMed 41645219

[Abstract]
BACKGROUND: This study investigated the relationship between the ketogenic diet, RGMa methylation, and GluA1 palmitoylation in a rat model of epilepsy, aiming to identify a novel mechanism for treating refractory epilepsy with the ketogenic diet. METHODS: Epileptic rats were treated with a ketogenic diet. Hippocampal tissue was analyzed to assess the expression of DNMT1 and DNMT3a proteins, RGMa DNA methylation and protein expression, FAK and zDHHC3 phosphorylation and expression, and GluA1 palmitoylation and expression. The therapeutic effects of the ketogenic diet on seizure frequency were statistically analyzed, along with the correlation between each parameter and treatment outcomes. RESULTS: The ketogenic diet treatment reduced seizure frequency in the epileptic rats. It inhibited RGMa DNA methylation in hippocampal tissue while increasing RGMa expression. Additionally, the diet enhanced GluA1 palmitoylation and reduced its expression on the neuronal membrane. These changes were associated with alterations in FAK/Src and zDHHC3 phosphorylation. CONCLUSION: The ketogenic diet inhibits RGMa DNA methylation, upregulates RGMa expression, and promotes GluA1 palmitoylation, leading to a reduction in seizure frequency and alleviation of refractory epilepsy in the rat model. These effects may be mediated through the RGMa-FAK/Src-zDHHC3 signaling axis.