UVB enhances SLC6A15-mediated phenylalanine transport to promote melanogenesis

Abnormal melanogenesis is a fundamental biological process underlying pigmentary disorders. While several solute carrier (SLC) transporters have been implicated in its regulation, the functions of many SLCs members remain poorly characterized.

We delineated transcriptional features of melanocytes with high melanogenic activity using single-cell and bulk RNA sequencing. Key SLC genes associated with melanogenesis were identified and prioritized using machine learning and Mendelian randomization analyses, followed by in vitro functional validation.

Integrated multi-omics analysis identified SLC6A15 as a potential regulator of melanogenesis. SLC6A15 knockdown in MNT1 cells and primary melanocytes reduced melanin synthesis and downregulated key melanogenesis-related genes (e.g., MITF, TYR, DCT). Fontana-Masson staining and tyrosinase activity assays confirmed a marked decrease in melanin deposition and TYR activity in SLC6A15-depleted cells. UVB exposure upregulated SLC6A15, whereas SLC6A15 silencing abrogated the UVB-induced increase in pigmentation. Mechanistically, SLC6A15 knockdown reduced intracellular phenylalanine levels, indicating a role for SLC6A15-mediated phenylalanine transport in melanogenesis. Mendelian randomization further suggested that genetically higher phenylalanine levels are associated with an increased risk of melasma (OR = 6.02).

Our findings identify SLC6A15 as a potential key regulator of melanogenesis through the transport of phenylalanine.