Multi-omics Analysis of the Palmitoylation Gene ZDHHC18 Regulating Sphingolipid Metabolic Homeostasis and Its Role in Epilepsy Pathogenesis

Introduction/Objective: Palmitoylation in neurodisorders is increasingly recognized, but the specific molecular mechanisms and metabolic networks underlying epileptic pathogenesis remain poorly understood. Using a multi-omics integrative strategy, this work intended to systematically examine the contribution of palmitoylation-related genes to epilepsy. Methods: We integrated Mendelian randomization (MR), transcriptomic profiling, and single-cell RNA sequencing. To this end, we used two-sample MR to screen for potential causal relationships among palmitoylation genes, plasma metabolites, and epilepsy. Then, we applied a mediation model to infer metabolic networks and used publicly available single-cell transcriptomic data to identify cell-type-specific expression of ZDHHC18. Results: In MR, ZDHHC18, ZDHHC19, and ZDHHC20 were implicated in epilepsy risk (p < 0.05). The patients’ peripheral blood transcriptomic data showed elevated ZDHHC18 expression (p < 0.05). Based on the mediation analysis, 57.51% of the effect from ZDHHC18 may have been mediated via the sphingolipid metabolite N-Palmitoyl-heptadecasphingosine (d17:1/16:0). Single-cell sequencing revealed dynamic ZDHHC18 expression in epilepsy in inhibitory neurons. We also found that these neurons are enriched for neural signaling and neuroinflammation pathways, and that the differentiation trajectory is correlated with the ZDHHC18 expression pattern. Discussion: From our integrative analysis, we propose a novel “ZDHHC18-sphingolipid” axis, suggesting that sphingolipid metabolic homeostasis disruption may be involved in the pathogenesis of epilepsy. Collectively, these findings yield a novel and testable genetic/metabolic/cellular hypothesis for epileptogenesis. Conclusion: This research found a link between ZDHHC18 and epilepsy, potentially via disruption of sphingolipid metabolic homeostasis, providing new molecular insights for developing targeted therapies.