microRNA miR-31-5p confers protection to melanin-deficient vitiligo keratinocytes against UV-B induced DNA damage by activating autophagy machinery

Despite lacking melanin, vitiligo skin paradoxically exhibits a lower incidence of non-melanoma skin cancers, indicating alternative epidermal defense mechanisms. We investigated the protective role of microRNA-31-5p (miR-31-5p), which is elevated in vitiligo lesions, against UV-B-induced DNA damage in keratinocytes. Primary human keratinocytes exposed to UV-B were treated with miR-31-5p mimic or antagomiR. miR-31-5p mimic significantly reduced DNA damage and increased the expression of nucleotide excision repair genes (DDB1, ERCC2, XPC), while alleviating replication stress. SP1 was identified as a direct target of miR-31-5p, and its suppression mirrored the DNA-protective effects. Importantly, miR-31-5p mimic robustly activated autophagy, as shown by increased expression of autophagy markers and enhanced autophagic flux; bafilomycin treatment further elevated LC3B and Beclin levels, indicating augmented autophagosome accumulation. Inhibition of autophagy with a ULK1 inhibitor abrogated the DNA-protective effects mediated by miR-31-5p mimic, confirming autophagy’s essential role. Analysis of lesional vitiligo epidermis revealed elevated miR-31-5p and reduced SP1 expression, consistent with in vitro findings. Our study identifies a novel miR-31-5p–SP1–autophagy–DNA repair axis in UV-B-exposed keratinocytes, providing new insight into melanin-independent epidermal protection in vitiligo and potential therapeutic strategies for enhancing UV resistance.