SVCT2-mediated ascorbic acid uptake buffers stress responses via DNA hydroxymethylation reprogramming of S100 calcium-binding protein A4 gene

Redox Biol. 2022 Dec;58:102543. doi: 10.1016/j.redox.2022.102543. Epub 2022 Nov 21.


Vitamin C, a key antioxidant in the central nervous system, cycles between ascorbic acid and dehydroascorbic acid under pathophysiological conditions. Clinical evidence supports that the absence of vitamin C may be linked to depressive symptoms, but much less is known about the mechanism. Herein, we show that chronic stress disrupts the expression of ascorbic acid transporter, sodium-dependent vitamin C transport 2, and induces a deficiency in endogenous ascorbic acid in the medial prefrontal cortex, leading to depressive-like behaviors by disturbing redox-dependent DNA methylation reprogramming. Attractively, ascorbic acid (100 mg/kg-1000 mg/kg, intraperitoneal injection, as bioequivalent of an intravenous drip dose of 0.48 g-4.8 g ascorbic acid per day in humans) produces rapid-acting antidepressant effects via triggering DNA demethylation catalyzed by ten-eleven translocation dioxygenases. In particular, the mechanistic studies by both transcriptome sequencing and methylation sequencing have shown that S100 calcium binding protein A4, a potentially protective factor against oxidative stress and brain injury, mediates the antidepressant activity of ascorbic acid via activating erb-b2 receptor tyrosine kinase 4 (ErbB4)-brain derived neurotrophic factor (BDNF) signaling pathway. Overall, our findings reveal a novel nutritional mechanism that couples stress to aberrant DNA methylation underlying depressive-like behaviors. Therefore, application of vitamin C may be a potential strategy for the treatment of depression.

Keywords: Ascorbic acid; Depression; Oxidative stress; S100 calcium binding protein A4; Sodium-dependent vitamin C transport 2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ascorbic Acid* / metabolism
  • Ascorbic Acid* / pharmacology
  • Biological Transport
  • DNA / metabolism
  • Humans
  • S100 Calcium-Binding Protein A4 / metabolism
  • Sodium-Coupled Vitamin C Transporters* / genetics
  • Sodium-Coupled Vitamin C Transporters* / metabolism


  • Ascorbic Acid
  • DNA
  • S100 Calcium-Binding Protein A4
  • Sodium-Coupled Vitamin C Transporters
  • SLC23A2 protein, human
  • S100A4 protein, human