STEAP4 Modulates Intestinal Barrier Dysfunction and Inflammatory Signaling Pathways in Ulcerative Colitis.

Ulcerative colitis (UC) is characterized by intestinal barrier dysfunction and chronic inflammation, yet its underlying mechanisms remain incompletely understood. This study investigates the role of six-transmembrane epithelial antigen of the prostate 4 (STEAP4), a metalloreductase linked to redox regulation, in UC pathogenesis. Using clinical samples from inflammatory bowel disease patients, a dextran sulfate sodium-induced murine colitis model, and lipopolysaccharide-treated intestinal epithelial cells (NCM460 and HT-29), we demonstrated that STEAP4 expression was significantly upregulated in inflamed mucosa across human, murine, and in vitro models. Hematoxylin and eosin staining and Western blot analyses verified the successful modeling of dextran sulfate sodium-induced colitis mice. STEAP4 knockdown via small interfering RNA restored tight junction protein claudin-1 expression ( P < 0.05; n = 3), increased transepithelial electrical resistance value ( P < 0.001; n = 3), decreased the permeability of fluorescein isothiocyanate (FITC)-D ( P < 0.01, P < 0.001; n = 3) and suppressed lipopolysaccharide-induced pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-6) ( P < 0.05; n = 3) by attenuating nuclear factor kappa-B phosphorylation (p65 and IκBα) ( P < 0.05, P < 0.01, P < 0.001; n = 3). These findings position STEAP4 as a critical regulator of mucosal inflammation, bridging redox homeostasis, epithelial barrier function, and nuclear factor kappa-B-driven immune responses. Our study highlights STEAP4 as a potential therapeutic target for restoring intestinal homeostasis in UC, warranting further exploration of its molecular interactions and translational applications.