Abstract / Summary
Circumferential endoscopic submucosal dissection (cESD) for superficially spreading esophageal cancer frequently results in esophageal strictures. Proton pump inhibitors (PPIs) possess anti-inflammatory and anti-fibrotic properties. This study aimed to investigate the efficacy and mechanisms of conventional acid-suppressing PPIs and a novel potassium-competitive acid blocker (PCAB) in treating esophageal strictures following cESD. Patients treated with the PPI esomeprazole, the PCAB vonoprazan, or no acid suppression were compared in terms of clinical outcomes, including stricture incidence. The number of endoscopic balloon dilations (EBDs) required, the time to esophageal stricture formation, and duration of EBDs were assessed. Human esophageal fibroblasts were cultured to examine the effects of PPIs and vonoprazan using real-time polymerase chain reaction, RNA sequencing, and immunofluorescence. Although neither agent prevented esophageal strictures, PPIs and vonoprazan prolonged the time to stricture. Esomeprazole significantly decreased both the frequency and duration of EBD sessions, whereas vonoprazan demonstrated comparable trends without reaching statistical significance. In vitro, esomeprazole and vonoprazan broadly influenced gene expression in human esophageal fibroblasts, including transcriptomic pathways associated with the cell cycle and apoptosis. A significant overlap in transcriptomic changes was observed between the two treatments, although esomeprazole had a broader and more pronounced effect. Esomeprazole more effectively reversed transforming growth factor-β-induced fibrotic responses compared with vonoprazan. These effects were dose-dependent and more evident when administered before transforming growth factor-β stimulation. We propose the use of PPIs or vonoprazan to attenuate esophageal strictures after cESD. Their mechanisms of action largely overlapped, and esomeprazole demonstrated broader anti-fibrotic effects in vitro with statistically significant reductions in EBD requirements. Higher doses and earlier initiation enhanced anti-fibrotic effects in vitro, highlighting the need for further clinical evaluation.