{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T16:42:31Z","timestamp":1792514551218,"version":"4.5.0"},"reference-count":38,"publisher":"S. Karger AG","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/karger.com\/pages\/terms-and-conditions"},{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/karger.com\/pages\/terms-and-conditions"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Digestion"],"abstract":"<jats:p>Introduction: The rising incidence and poor prognosis of esophageal adenocarcinoma (EAC) highlight the urgent need to identify novel molecular determinants. Ribosome heterogeneity has emerged as a potential factor in carcinogenesis, yet its causal relevance in EAC remains unclear. We aimed to systematically evaluate the causal effects of ribosome-related genes on EAC risk by integrating multi-omics data. Methods: We applied summary-data-based Mendelian randomization (SMR) to analyze 1,329 ribosome-related genes, integrating mQTL, eQTL, pQTL data, and a large EAC GWAS. Bayesian colocalization and esophageal tissue transcriptome analyses validated causal signals. We compared mRNA\/protein levels of candidate genes in normal HET-1A esophageal cells versus EAC cell lines OE33 and OE19 and validated methylation-gene correlations using the TCGA-ESCA cohort. Crucially, functional assays, including CCK-8, Transwell, colony formation, and apoptosis assays, were performed in OE33 cells following gene overexpression to verify their causal roles. Results: SMR analyses identified EIF2B2 and RPS6KL1 as causal protective genes for EAC; genetically elevated expression of both reduced EAC risk. A regulatory cascade was uncovered, whereby specific CpG methylation repressed gene transcription to alter disease susceptibility. Consistently, EIF2B2 and RPS6KL1 mRNA and protein were markedly lower in OE33\/OE19 tumor cells than HET-1A. TCGA data confirmed negative correlation between RPS6KL1 promoter cg19899223 methylation and gene expression (\u03c1 = \u22120.27, p = 0.00015). Functionally, overexpression of EIF2B2 and RPS6KL1 in OE33 cells significantly suppressed cell viability, invasion, and colony formation, while inducing apoptosis, thereby experimentally validating their tumor-suppressive effects. Conclusion: By integrating multi-omics evidence with functional assays, this study identifies EIF2B2 and RPS6KL1 as causal protective factors in EAC etiology. These findings suggest that maintaining ribosomal homeostasis via these genes acts as a barrier against EAC, highlighting their potential for risk stratification and therapeutic targeting.<\/jats:p>","DOI":"10.1159\/dig\/acmag020","type":"journal-article","created":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T11:23:32Z","timestamp":1789903412000},"page":"1-1","source":"Crossref","is-referenced-by-count":0,"title":["Epigenetic and Transcriptional Dysregulation of Ribosomal Genes in Esophageal Adenocarcinoma: A Multi-Omics Mendelian Randomization 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