Identification of LPO and RTN4R as Proteomic Signatures of Pain Persistence: An Exploratory Analysis of the UK Biobank

BackgroundThe transition from acute to chronic pain represents a failure of physiological resolution. While systemic immune cell counts and androgen levels have been associated with this transition, the specific molecular mediators remain poorly understood. We sought to identify the functional proteomic drivers of long-term pain persistence and determine their independence from systemic factors. MethodsWe identified a longitudinal persistence cohort (N=3,221) within the UK Biobank who reported acute pain at baseline and were followed for resolution or persistence. Using the Olink Explore 3072 platform, we screened 2,923 serum proteins. Multivariable competition models were employed to evaluate the independent predictive power of top proteomic hits alongside systemic monocyte counts and circulating free testosterone levels, adjusted for age and sex. ResultsOur proteome-wide screen identified Lactoperoxidase (LPO) as a dominant and highly significant predictor of pain persistence. In the fully adjusted competition model, each standard deviation increase in LPO was associated with a 59% increase in the odds of persistence (OR 1.59, 95% CI 1.25-2.07, p < 0.001). Notably, after accounting for LPO, systemic monocyte counts (OR 0.93, p = 0.55) and testosterone levels (OR 0.82, p = 0.46) were no longer significant predictors. Nogo Receptor (RTN4R) also remained a significant predictor in independent models (OR 1.44, p = 0.002). ConclusionsThese exploratory findings demonstrate that long-term pain persistence is associated with specific functional molecular signatures rather than broad systemic cell quantity. The dominance of LPO suggests that secretory peroxidase-driven pathways may be a primary barrier to pain resolution. Furthermore, the association of RTN4R identifies neural repair inhibition as a candidate driver of persistence. These proteins are candidates for further mechanistic investigation.