Mechanistic Insights into Drug-Induced Guillain–Barré Syndrome: A Large-Cohort Analysis of the FAERS Database

<b>Background/Objectives</b>: Drug-induced Guillain-Barré Syndrome (GBS) is a severe complication of pharmacotherapy. Previous research has established a connection between certain medications and higher GBS risk. However, a large-cohort analysis is crucial to reveal underlying biological mechanisms of drug-induced GBS. This study aimed to evaluate the association between GBS and various drugs currently accessible in the Food and Drug Administration Adverse Event Reporting System (FAERS) database and explore the mechanisms underlying drug-induced GBS. <b>Methods</b>: We analyzed drug-induced GBS adverse event reports in the FAERS database to identify strongly associated drugs. We then investigated GBS susceptibility proteins through GWAS meta-analysis and Mendelian Randomization (MR) based on plasma proteomics, complemented by protein-protein interaction (PPI) network analysis to explore underlying mechanisms. <b>Results</b>: A total of 4094 FAERS reports were analyzed, leading to the selection of 30 drugs with the highest signal strength and 54 drug targets. MR analysis identified 73 susceptibility proteins linked to GBS risk. PPI analysis revealed that 10 genes encoding GBS-susceptible proteins were associated with 19 drug target genes involved in 13 different drugs. Among these, the antineoplastic drug Nelarabine showed the strongest correlation with GBS. The <i>TNF</i> and <i>PDCD1LG2</i> genes emerged as key GBS-susceptible genes. Additionally, <i>TNF</i> was negatively correlated with GBS, and <i>PDCD1LG2</i> was positively correlated with GBS. KEGG analysis indicated that pyrimidine metabolism, purine metabolism, and the IL6/JAK/STAT3 signaling pathway also significantly contribute to drug-induced GBS. <b>Conclusions</b>: This study improved our understanding of the biological mechanisms of drug-induced GBS, thereby pinpointing potential therapeutic targets for future intervention.