OPN3 is a G protein-coupled receptor that functions as a light-dependent and light-independent photoreceptor with diverse roles in skin physiology and systemic homeostasis. As a photoreceptor, OPN3 selectively activates Gi/o proteins in response to ultraviolet A and blue light, decreasing cellular cAMP levels 12. The protein binds both 11-cis and all-trans retinal 3, though certain missense mutations severely impair retinal binding and calcium signaling 4. In melanocytes, OPN3 regulates melanogenesis through both light-independent and light-dependent mechanisms by inhibiting MC1R-evoked cAMP signaling and modulating calcium-dependent kinase pathways 13. OPN3 also interacts functionally with BRAFV600E signaling in congenital melanocytic nevus cells 5. Beyond pigmentation, OPN3 promotes melanocyte survival via intracellular calcium regulation and BCL2/RAF1 signaling 6. In keratinocytes, light-induced OPN3 activation triggers proinflammatory cytokine production through calcium influx and sphingosine 1-phosphate signaling, exaggerating atopic dermatitis 7. In the hypothalamic paraventricular nucleus, OPN3 suppresses MC4R signaling and potentiates Kir7.1 channel activity to promote food intake 8. Additionally, OPN3 promotes angiogenesis in endothelial cells through VEGFR2 interaction 9. High OPN3 expression associates with poor prognosis in multiple cancer types 1011.