A viral-host redox axis: EBNA1-FOSL2-ALDH3A1 defines a targetable vulnerability in EBV-positive carcinomas.

Epstein-Barr virus (EBV)-associated carcinomas exhibit reprogrammed redox metabolism, yet the underlying regulatory network and potential metabolic vulnerabilities remain incompletely defined. Here we identify a viral-host transcriptional axis in which EBV EBNA1 induces the transcription factor FOSL2 to repress ALDH3A1. Restoration of ALDH3A1 in EBV-positive models disrupts NAD(P)H/NAD(P)+ homeostasis, inducing reductive stress. This reductive milieu upregulates GSNOR and TrxR1, potentiating the denitrosylation of GSK3β, leading to its stabilization and suppression of the Wnt/β-catenin pathway. We establish that S-nitrosylation at GSK3β Cys199 controls its stability, providing a mechanistic bridge from redox regulation to Wnt inhibition. Critically, ALDH3A1 elevation selectively curbs EBV-positive tumor growth, exploiting an infection-specific vulnerability in redox signaling. Thus, our findings integrate EBV-driven redox remodeling with Wnt/β-catenin signaling activation and propose ALDH3A1 induction as a promising therapeutic strategy for EBV-associated carcinomas.