Ascorbate is an essential cofactor for TET enzymes and other α-KG-dependent dioxygenases. High-dose supplementation has been proposed to partially overcome succinate-mediated TET inhibition, restoring some DNA demethylation activity, and to generate ROS at pharmacological doses with potential anti-tumor activity. HOWEVER — CRITICAL SAFETY SIGNAL: Rapizzi et al. (Endocr Relat Cancer 2026, PMID 41404848) demonstrated that vitamin C supplementation PROMOTED tumor growth in a SDHB-deficient pheochromocytoma/paraganglioma zebrafish model rather than suppressing it. This is directly opposite to the hypothesized TET-rescue benefit. Plausible mechanisms for the pro-tumorigenic effect include: (1) in the pseudohypoxic, HIF-1α-stabilized SDH-deficient context, restored TET activity from ascorbate supplementation may reactivate pro-survival and pro-proliferative gene programs that are normally silenced by CIMP hypermethylation; (2) ascorbate-driven ROS generation may paradoxically activate HIF-1α-dependent survival pathways; (3) ascorbate may support anaplerotic aspartate or one-carbon metabolism pathways that sustain cell growth. This finding is clinically critical for SDH-deficient patients: high-dose vitamin C supplementation (whether oral or IV) should be considered potentially counterproductive until dedicated in-vivo data from SDHA-deficient GIST models or prospective clinical studies are available. The evidence score has been downgraded accordingly; this drug entry is retained for reference and to flag the safety concern.