prognostic significance of nfe2l2 and its gene signature in esophageal squamous cell carcinoma: a multi-omics approach

Esophageal squamous cell carcinoma (escc) is a globally prevalent and aggressive malignancy with an urgent need for robust prognostic biomarkers to guide patient stratification and treatment. this study explores the potential of transcription factors (tfs)—particularly nfe2l2—as prognostic markers in escc through integrated multi-omics analysis. we hypothesized that nfe2l2 mutation status and its downstream targets could form a novel prognostic signature for patient survival. using publicly available data from tcga via cbioportal, we identified frequently mutated tfs in escc, prioritizing nfe2l2, which showed a 17% mutation frequency. transcriptomic analysis of nfe2l2 perturbation (linkedomics) revealed 20 differentially expressed genes (degs) (log-fc ≥ 1.25, p ≤ 0.05). kaplan-meier survival analysis (kmplotter) was used to assess their prognostic significance. all 20 nfe2l2-associated degs were significantly linked to escc patient survival. notably, downregulated genes including birc3 (hr = 0.37), ca3 (hr = 0.18), and muc6 (hr = 0.38) paradoxically correlated with improved survival (hr < 1). in contrast, upregulated genes such as mpp3 and fjx1 showed a trend toward poorer survival (hr ≥ 1). the strong protective effect associated with the downregulation of birc3, ca3, and muc6 in the context of nfe2l2 activity is particularly noteworthy. this multi-omics analysis identifies nfe2l2 as a critical prognostic biomarker in escc. the associated gene signature-especially the survival benefit linked to the downregulation of key genes-offers novel insights into escc biology. these findings highlight nfe2l2 and its regulatory network as promising prognostic indicators and potential therapeutic targets, meriting further mechanistic exploration and clinical validation.