Proteomic analysis further revealed that RHBDF2 was downregulated and could serve as a potential biomarker for the disease.<h4>Conclusions</h4>This study provides robust epidemiological and molecular evidence for esophageal cancer prevention and early intervention strategies, and the identified potential biomarker RHBDF2 and high-performance predictive model offer valuable tools for the early detection of esophageal cancer in high-risk regions of Northwest China. This evidence concerns the gene RHBDF2 and esophageal cancer.