A viral–host redox axis: EBNA1–FOSL2–ALDH3A1 defines a targetable vulnerability in EBV-positive carcinomas
Year: 2026
Type: article
Abstract: 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. • ALDH3A1 specifically suppresses the proliferation of EBV-positive carcinomas • EBNA1 transcriptionally represses ALDH3A1 via upregulating FOSL2 in EBV-positive carcinomas • In EBV-positive carcinomas, ALDH3A1 induces reductive stress—manifested as an altered NADH/NAD + ratio and consequent remodeling of the denitrosylation landscape • ALDH3A1 enhances GSK3β stability by preventing its nitrosylation at the C199 site, thereby promoting β-catenin degradation
Source: Redox Biology
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,310
Awards: G2802848135, G8262701116
OpenAlex ID: W7123654160