S100A12 correlates with inflammatory and pain symptoms in patients with chronic prostatitis/chronic pelvic pain syndrome

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is the most prevalent urological condition in men under 50, characterized by persistent or recurrent pelvic and perineal pain, and significantly reduced quality of life. Reliable biomarkers for assessment and mechanistic understanding of pain remain limited. This retrospective case-control study consisting of 90 CP/CPPS patients (median age 29.4 years) and 90 age-matched healthy controls investigated the alarmin S100A12 as a potential biomarker linking inflammation to neurogenic pain. Seminal plasma, serum, and post-prostatic massage (PPM) urine samples were analyzed. S100A12 levels were significantly elevated in patients in seminal plasma (median 47.8 vs. 2.5 ng/ml, p<0.001) and serum (median 49.2 vs. 17.4 ng/ml, p<0.001). Seminal S100A12 correlated with inflammatory markers (ρ=0.551-0.686), CPSI pain scores (ρ=0.451, p<0.001), and IPSS (ρ=0.342, p=0.001). Receiver operating characteristic analysis demonstrated superior diagnostic performance for seminal S100A12 (AUC=0.90, 95% CI: 0.77-0.93) compared to leukocyte count (AUC=0.60), IL-8 (AUC=0.70), and granulocyte elastase (AUC=0.50). S100A12 also correlated with sperm tail defects (ρ=0.445, p<0.001), and inversely with motility (ρ=-0.306, p=0.003) and vitality (ρ=-0.273, p=0.005). In silico analysis of prostate single-cell RNA sequencing data identified S100A12-expressing CXCR1+ myeloid cells, suggesting a link to IL-8-mediated inflammation. PPM urine-derived leukocytes from patients showed increased expression of RAGE (p=0.006) and CALCA (p<0.001), correlating with pain severity (ρ=0.541, p<0.001). These findings implicate S100A12 in leukocyte-nerve interactions underlying pelvic pain and dysfunction, and support its use as a diagnostic biomarker and potential therapeutic target in CP/CPPS. PERSPECTIVE: This study identifies S100A12 as a potential biomarker of inflammation and pain in young CP/CPPS patients. The findings suggest a neuroimmune interaction involving S100A12, RAGE, and CGRP/NGF signaling, which may guide future patient stratification and therapeutic development targeting pain chronicity, inflammation, and reproductive dysfunction in CP/CPPS.