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 IBD patients, a dextran sulfate sodium (DSS)-induced murine colitis model, and lipopolysaccharide (LPS)-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. H&E staining, and Western blot analyses verified the successful modeling of DSS-induced colitis mice. STEAP4 knockdown via siRNA restored tight junction protein claudin-1 expression (p < 0.05; n=3), increased TEER value (p < 0.001; n=3), decreased the permeability of FITC-D (p < 0.01, p < 0.001; n=3) and suppressed LPS-induced pro-inflammatory cytokines (TNF-α, IL-6) (p < 0.05; n=3) by attenuating NF-κB phosphorylation (p65, 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 NF-κB-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.