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Ascorbic Acid (High-dose IV)

TET enzyme cofactor / α-KG-dependent dioxygenase activator

Evidence Score

38

preclinical
Mechanism of Action

Ascorbate is an essential cofactor for TET enzymes and other α-KG-dependent dioxygenases. High-dose supplementation may partially overcome succinate-mediated inhibition of TETs, restoring some DNA demethylation activity. Also generates ROS at pharmacological doses.

Pathway Connections
Epigenetic Dysregulation

Succinate inhibits TET family DNA demethylases and Jumonji-domain histone demethylases, causing global DNA and histone hypermethylation. This silences tumor suppressors and blocks differentiation.

Upstream event:

Succinate inhibits TET1/2/3 and KDM histone demethylases

Downstream effects:

DNA hypermethylation (CIMP phenotype)5-hydroxymethylcytosine lossTumor suppressor silencingHistone hypermethylationDifferentiation block
Oxidative Stress / ROS

Complex II dysfunction causes electron leak in the electron transport chain, increasing reactive oxygen species (ROS). This drives DNA damage but also creates a therapeutic vulnerability.

Upstream event:

Impaired electron flow through Complex II → electron leak

Downstream effects:

Increased ROS productionOxidative DNA damageGenomic instabilityPARP activation for DNA repairTherapeutic vulnerability to further ROS stress
Molecular Targets

TET2

Tet methylcytosine dioxygenase 2

direct

α-KG-dependent DNA demethylase directly inhibited by succinate. Its inhibition drives the CIMP phenotype.

UniProt: Q6N021

Quick Facts
Not FDA Approved
ChEMBL IDCHEMBL196
PubChem CID54670067
Evidence

Evidence from PubMed, OpenTargets, and ChEMBL will appear here once external data integration is enabled.

Coming in Phase 3

For research exploration only — not medical advice. Consult your doctor before acting on any information.

AI Analysis

Have Claude analyze this drug's repurposing potential for SDH-deficient diseases.