Current biomarkers, including serum C-reactive protein (CRP) and fecal calprotectin, have limitations in monitoring disease activity of ulcerative colitis (UC). Regenerating islet-derived protein 3\(\alpha\) (REG3\(\alpha\)), which is constitutively produced by Paneth cells, is a bactericidal C-type protein against Gram-positive bacteria. Preliminary studies suggest that REG3\(\alpha\) may serve as a promising novel blood-based biomarker for assessing disease activity in patients with UC. A total of 128 patients with UC were prospectively enrolled. Blood samples were obtained on the same day as endoscopy. Serological markers including REG3\(\alpha\), CRP, albumin, and serum calprotectin were measured. The clinical and endoscopic activity were assessed using the total Mayo score (remission, mild, or moderate-to-severe) and the Mayo endoscopic subscore (MES), respectively. Serum levels of REG3\(\alpha\), CRP, albumin, and calprotectin were significantly correlated with clinical activity (Mayo score ≥ 6) (Spearman’s ρ = 0.362, P < 0.001; ρ = 0.429, P < 0.001; ρ = −0.312, P < 0.001; and ρ = 0.253, P = 0.004, respectively). Serum levels of REG3\(\alpha\), CRP, and albumin were also significantly correlated with endoscopic activity (MES ≥ 2) (ρ = 0.362, P < 0.001; ρ = 0.420, P < 0.001; and ρ = −0.240, P = 0.006, respectively), whereas serum calprotectin was not (ρ = 0.147, P = 0.098). The combination of serum REG3\(\alpha\) and CRP predicted clinical and endoscopic activity with AUC values of 0.847 and 0.783, respectively, showing improved discriminatory performance compared with the individual biomarkers in this cohort. Among 19 patients who underwent serial follow-up of REG3\(\alpha\) levels, a significant decrease was observed during periods of clinical improvement (P = 0.005), although this finding should be interpreted as preliminary. REG3\(\alpha\) is a promising blood-based biomarker associated with both clinical and endoscopic activity in UC. When interpreted together with CRP, it showed improved discriminatory performance in this cohort. This serum-based approach may be useful as an adjunctive option when stool-based testing is less feasible. However, the combined REG3\(\alpha\)–CRP model should be considered exploratory, and the serial monitoring findings should be interpreted as preliminary. Further validation in larger, independent cohorts, including direct comparison with fecal calprotectin, is required before broader clinical application can be considered.
