Vitamin C Promotes Epidermal Regeneration Through Epigenetic Mechanisms

As the body’s largest organ, the skin serves as a vital barrier against environmental stressors. With age, the skin’s outermost layer – the epidermis – gradually thins, weakening its ability to protect underlying tissues. This layer primarily comprises keratinocytes, which originate in deeper layers and migrate outward, where they form the skin’s protective barrier.

Recent research from Japan has shown that vitamin C helps restore the thickness of the epidermis by activating genes that control keratinocyte growth and maturation. The study, published in the Journal of Investigative Dermatology on April 20, 2025, offers molecular insights into how vitamin C contributes to skin regeneration.

Laboratory-grown skin models replicate epidermal responses

The researchers used human epidermal equivalents – 3D culture models that replicate real human skin – to assess how vitamin C affects epidermal structure. These models expose skin cells to air while providing nutrients from below, closely mimicking natural conditions.

Vitamin C was applied to the models at concentrations of 0.1 and 1.0 mM, approximating levels transported from the bloodstream to the skin. By day seven, treated samples showed a thicker basal layer without changes to the stratum corneum, the outermost layer of dead cells. By day 14, the basal layer was further thickened, while the outer layer was thinner. This suggests vitamin C promotes keratinocyte proliferation and turnover.

Cell division is increased by epigenetic reprogramming

Keratinocyte proliferation was confirmed by the increased presence of Ki-67, a nuclear marker expressed in actively dividing cells. Importantly, vitamin C did not merely act as an antioxidant but played a direct role in gene regulation.

The study found that vitamin C enhanced the expression of genes involved in cell proliferation through DNA demethylation. DNA methylation involves the addition of methyl groups to cytosine bases, often suppressing gene activity. Removal of these groups – a process called demethylation – can reactivate silenced genes.

Vitamin C supports this process by maintaining the activity of ten-eleven translocation (TET) enzymes, which catalyze the conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC). This oxidation reaction depends on Fe2+, which is oxidized to Fe3+ during the process. Vitamin C restores Fe2+ by donating electrons, enabling continued enzymatic activity.

Genomic analysis confirms demethylation and gene upregulation

Genome-wide methylation analysis revealed more than 10,000 differentially methylated regions with reduced methylation in vitamin C-treated samples. Among these, 12 genes associated with cell division showed 1.6- to 75.2-fold increased expression.

When the TET enzyme activity was inhibited, the effects of vitamin C on both DNA methylation and gene expression were reversed, confirming that vitamin C acts through a TET-mediated mechanism.

Potential applications for skin regeneration

While the study did not investigate human subjects, the findings suggest that vitamin C could enhance epidermal regeneration in conditions marked by skin thinning. By modulating gene expression through epigenetic mechanisms, vitamin C may improve skin structure and function, particularly in older adults or individuals with damaged skin.

Reference: Sato Y, Sato A, Florence, et al. Vitamin C promotes epidermal proliferation by promoting DNA demethylation of proliferation-related genes in human epidermal equivalents. J Investigat Dermatol. 2025:S0022202X25004166. doi: 10.1016/j.jid.2025.03.040

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