Pathology-Driven Epithelial Sulfide Loss Reprograms the Redox Proteome and Triggers Barrett's Esophagus.

BACKGROUND & AIMS: Barrett's esophagus (BE), a metaplastic transformation driven by gastroesophageal reflux disease (GERD), induces oxidative stress but the underlying redox mechanisms remain poorly understood. Protein persulfidation (PSSH), a redox-sensitive, reversible, and antioxidative post-translational modification regulated by hydrogen sulfide (H2S) metabolism, has not been explored in this context. Here, we identify epithelial PSSH as a key regulator of this premalignant process.

METHODS

We applied proteomics and chemoproteomics in 2 patient cohorts to map and validate PSSH and total proteome profiles across healthy (squamous), GERD-exposed, and metaplastic epithelium. Using in vitro and in vivo models of chronic GERD and BE, we modulated H2S levels genetically and pharmacologically. Mechanistic and functional effects were assessed using tissue biopsies or recombinant human proteins.

RESULTS

GERD-induced oxidative loss of H2S and its enhanced catabolism initiated early PSSH proteome remodeling in squamous epithelium, which expanded in BE and affected >1300 proteins in clinical samples, indicating potential biomarkers. This also included altered persulfidation of enzymes regulating accumulation of prostaglandin E2 (PGE2), a well-established driver of BE development and progression. H2S depletion accelerated metaplastic transformation, whereas H2S donors reversed these effects in experimental models. PSSH of 15-hydroxyprostaglandin dehydrogenase reversibly suppressed its activity, protecting the enzyme and, unlike irreversible oxidation, allowing recovery of PGE2 degradation.

CONCLUSIONS

These findings redefine the origin of PGE2 accumulation in metaplasia and establish sulfide loss and persulfidomic remodeling as central, druggable drivers of epithelial reprogramming and redox imbalance in BE pathogenesis.