OPN3, as a member of the opsin family, has various nonlight-dependent functions. Congenital melanocytic nevus (CMN) is a skin lesion with dark pigmentation that appears at birth and can be initiated by the BRAFV600E mutation in melanocytes. However, the role of OPN3 in BRAFV600E CMN cell melanogenesis has never been reported. In this study, we show that OPN3 acts as a negative regulator of melanin production by modulating BRAFV600E signaling in BRAFV600E CMN cells. Knocking down OPN3 expression can inhibit the BRAFV600E/extracellular signal‒regulated kinase signaling pathway and upregulate the expression of microcephaly-related transcription factors, tyrosinase, and TRP1 and TRP2, thus increasing melanin levels in BRAFV600E CMN cells. More remarkably, OPN3 and BRAFV600E were found to form a physical complex. Furthermore, a three-dimensional nevus model was used to further prove the negative regulatory effect of OPN3 on BRAFV600E CMN cell melanogenesis. Our study reveals a mechanism for OPN3-mediated melanogenesis in BRAFV600E CMN cells, and these results may lead to a more personalized and economically viable approach to treating BRAFV600E CMN.
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