Nrf2 Activation Induces Fibroblast Senescence and Promotes Melanosome Accumulation in a Fibroblast-Keratinocyte Co-Culture Model

Solar lentigo (SL) is an age-associated hyperpigmented skin disorder linked to oxidative stress, impaired autophagy, and cellular senescence. However, experimental systems that recapitulate the senescence-associated skin microenvironment remain limited. In this study, we investigated the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in fibroblast senescence and pigmentation-related responses using transcriptomic analyses and a fibroblast-keratinocyte co-culture model. Public transcriptomic datasets revealed increased NFE2L2 expression together with altered autophagy-related and senescence-associated signatures in hyperpigmented skin lesions. In dermal fibroblasts, Nrf2 overexpression induced senescence-associated phenotypes, including increased SA-β-gal activity and elevated expression of SASP-related genes. In a fibroblast-keratinocyte co-culture system, Nrf2-activated fibroblasts promoted melanosome accumulation in keratinocytes, suggesting that senescence-associated dermal-epidermal interactions contribute to pigmentation-related alterations. SENOMUNE, a formulation with autophagy-modulating activity, enhanced LC3 puncta formation in keratinocytes and attenuated melanosome accumulation in the senescence-associated co-culture system. Collectively, these findings suggest that sustained Nrf2 activation contributes to fibroblast senescence and pigmentation-related responses and provide a useful co-culture platform for evaluating senescence-associated pigmentation modulators.