Abstract
Neurosyphilis (NS) is a chronic central nervous system infection caused by Treponema pallidum. Owing to its diverse clinical manifestations and the limited sensitivity of current diagnostic methods, NS is difficult to diagnose. Understanding the molecular mechanisms of NS and identifying reliable biomarkers are essential for improving diagnostic and therapeutic strategies. This study employed Mendelian randomization (MR) analysis to explore the causal relationships among protein ratio quantitative trait loci (rQTLs), cerebrospinal fluid (CSF) metabolites, and syphilis risk at various stages. The results revealed that several rQTLs, including CD46/TNFRSF14 and TBC1D23/TBC1D5, were closely associated with syphilis risk, whereas others, such as BANK1/HEXIM1 and GOPC/HEXIM1, exhibited protective effects. Mediation analysis further identified key CSF metabolites, such as N-acetyltaurine and bilirubin, as important mediators linking rQTLs and syphilis progression. Through integrated analysis of cis-proteins from rQTLs and transcriptomic data from CD4 + T-cells of NS patients, METAP2 was identified as a key biomarker in NS, with the potential mechanisms elucidated. Importantly, T. pallidum may inhibit CD4 + T-cell proliferation by modulating METAP2, thereby accelerating disease progression. These findings offer new insights into the pathogenesis of NS and highlight METAP2 as a potential biomarker, laying a foundation for improving diagnostic and therapeutic strategies.