A soluble form of 5-methyltetrahydrofolate modulates UVA-induced oxidative stress and cellular recovery processes in human dermal fibroblasts.

One-carbon metabolism supports nucleotide synthesis and methylation reactions, which are fundamental for cellular homeostasis and repair. The biologically active folate 5-methyltetrahydrofolate (5-MTHF) may help counteract UVA-induced stress in human dermal fibroblasts (HDF) and support their recovery. To test this hypothesis, HDF were treated with 5-MTHF in both preventive and rescue models, in which UVA was used to induce cellular stress. Fibroblasts showed a dose-dependent uptake of exogenous 5-MTHF, and intracellular 5-MTHF levels remained elevated for up to 48 h following supplementation. UVA irradiation caused a marked depletion of endogenous intracellular 5-MTHF, with a 57% reduction immediately after exposure and a 63% reduction after 24 h, whereas supplementation before or after UVA restored intracellular levels. Moreover, 5-MTHF improved cellular resilience following UVA exposure by attenuating CM-H2DCFDA- and MitoSOX-derived fluorescence, decreasing DNA damage detected by the comet assay, and improving fibroblast monolayer gap-closure. In the rescue model, 5-MTHF also partially restored COL1A1 abundance and attenuated MMP1 induction. Pre-treatment produced an earlier improvement in gap-closure, whereas post-treatment favoured recovery at later time points; at 48 h, 50 μM 5-MTHF increased closure by approximately 18 and 20 percentage points in the preventive and rescue models, respectively. Overall, the study provides evidence of an association linking intracellular 5-MTHF availability with improved cellular viability and functional recovery of fibroblasts under UVA stress. These findings support further investigation of 5-MTHF as a nutritional factor potentially contributing to skin resilience against photo-oxidative stress.