Abstract

Background Cluster headache (CH) is a highly disabling primary headache disorder with a complex underlying mechanism. However, there are currently no effective targeted therapeutic drugs available. Existing medications often have limited efficacy and numerous side effects, which frequently fail to meet clinical needs. This study aims to identify potential new therapeutic targets for CH through proteome-wide mendelian randomization (PWMR). Methods We used PWMR to estimate the causal effects of plasma proteins on CH. This analysis integrated plasma protein quantitative trait loci (pQTL) data with genome-wide association study (GWAS) results of CH phenotypes. In addition, we conducted various sensitivity analyses, enrichment analyses, phenome-wide MR assessments, protein–protein interaction network construction, and mediation MR analyses to further validate the drug potential of the identified protein targets. Results We identified 11 protein targets for CH (p < 2.41 × 10–5), with high-priority candidates exhibiting minimal side effects. Phenome-wide MR revealed novel targets—PXDNL, CCN4, PKD1, LGALS9, and MRC1—that show no significant disease-related adverse effects and interact with established preventive CH drug targets. Notably, PXDNL interacts with both acute and preventive CH drug targets. Furthermore, the causal effect of plasma proteins on CH is partially mediated by cortical surface area, with mediation proportions ranging from 3.2% to 10.0%. Conclusions We identified a set of potential protein targets for CH, characterized by rare side effects and a strong association with the biological mechanisms underlying the disorder. These findings offer valuable insights for the development of targeted drug therapies in the treatment of CH.