The study examined molecular responses in grapevine leaves with and without esca symptoms, using metabolite profiling, RNA‑seq and whole‑genome bisulfite sequencing. Metabolic and transcriptomic changes were confined to symptomatic leaves and linked to local DNA‑methylation alterations, while asymptomatic leaves showed distinct but overlapping methylation patterns, some present before symptoms, indicating potential epigenetic biomarkers for early disease detection.