Integrative transcriptomics and reverse network pharmacology prioritize DPP4 and Achyranthes bidentata in Barrett’s esophagus

Barrett's esophagus (BE) is a precursor of esophageal adenocarcinoma, but candidate expression markers and preventive hypotheses require evaluation across patients, cohorts, and evidence levels. We analyzed two GPL96 discovery cohorts comprising 15 matched normal–BE pairs, used pair-aware differential modeling and resampling, and rebuilt four external BE-tissue assessments from official GEO files. The primary analysis yielded 1,085 differentially expressed genes; LASSO selected 13 features, linear SVM-RFE selected 6, and pair-bootstrap Random Forest retained 20. DPP4 and CCRL2 were shared by the three primary feature sets, but not after phenotype-preserving ComBat sensitivity analysis. External Affymetrix AUCs were 1.000, 0.855, and 0.976 for DPP4 and 1.000, 0.858, and 0.963 for CCRL2. In the Illumina GSE28302 cohort, fixed-direction DPP4 AUC was 0.444 and CCRL2 lacked a uniquely mapped probe. Seventy-nine DEGs intersected the verified 710-gene disease union; STRING/CTD analysis ranked Niuxi, Mahuang, and Mahuanggen first through third. Reference-controlled docking advanced kaempferol–PPARG as the primary structural hypothesis and taxifolin–NQO1 as a secondary extension. Twelve 100 ns trajectories retained pocket-region contacts, but query compounds showed greater pose rearrangement than the reference ligands. These findings prioritize candidates for experimental validation and do not establish a diagnostic test, direct binding, expression reversal, or therapeutic efficacy.