NF-κB-Mediated Disruption of Key Transcription Factors Predisposes Lower Esophageal Squamous Epithelium to Esophageal Adenocarcinoma: a systematic review

ObjectiveThe objective of this study is to determine how NF-{kappa}B-mediated transcriptional disruption of key transcription factors (TP63, SOX2, KLF4, GRHL3, ELF3, TFAP2C, RUNX1, and ZBED2) in esophageal squamous stratified epithelium leads to the Esophageal Adenocarcinoma development. BackgroundChronic inflammation-driven NF-{kappa}B activation disrupts key transcription factors (TP63, SOX2, KLF4, GRHL3, ELF3, TFAP2C, RUNX1, ZBED2) essential for maintaining lower esophageal squamous epithelium (SSE). This dysregulation impairs differentiation, promotes oncogenic plasticity, and enables Barretts metaplasia, predisposing to esophageal adenocarcinoma. Understanding these mechanisms is vital for identifying biomarkers, restoring squamous identity, and developing targeted therapies to prevent malignant transformation and improve early detection of esophageal cancer. MethodsDatabases, including PubMed, MEDLINE, Google Scholar, and both open-access and subscription-based journals, were searched without date restrictions to investigate how NF-{kappa}B-mediated disruption of key transcription factors (TP63, SOX2, KLF4, GRHL3, ELF3, TFAP2C, RUNX1, ZBED2) in esophageal squamous stratified epithelium predisposes it to the development of esophageal adenocarcinoma. Studies meeting the criteria outlined in the methods section were systematically reviewed to address the research question. This study adheres to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. ResultsNF-{kappa}B disrupts key transcription factors critical for maintaining esophageal squamous identity, driving a shift toward esophageal adenocarcinoma. TP63, SOX2, and KLF4 loss weakens squamous fate, increasing plasticity. GRHL3, ELF3, and TFAP2C disruption impairs differentiation, promoting instability. RUNX1 downregulation disrupts homeostasis, while ZBED2 suppression enables columnar transformation via HNF4A activation. Chronic inflammation exacerbates these changes, fostering metaplasia and malignant progression. Understanding these mechanisms is possibly critical for developing therapies that restore transcriptional balance, block Barretts metaplasia, and prevent esophageal adenocarcinoma. ConclusionEsophageal adenocarcinoma arises from NF-{kappa}B-driven dysregulation of key transcription factors essential for maintaining squamous cell identity. Chronic inflammation damages TP63, SOX2, KLF4, GRHL3, ELF3, TFAP2C, RUNX1, and ZBED2, disrupting epithelial homeostasis and enabling Barretts metaplasia. Loss of squamous differentiation and activation of columnar pathways promote oncogenic transformation. Persistent NF-{kappa}B signaling fuels genetic instability, increasing malignancy risk. Targeting NF-{kappa}B or restoring these transcriptional regulators may prevent esophageal squamous-to-columnar transition, offering therapeutic potential against esophageal adenocarcinoma development and progression.