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Peer-reviewedCC BY-NC 4.0Biomolecules & Therapeutics

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

  • Ji Hye Yoon1
  • In Seop Kil2
  • Siyoung Cho2
  • Sunyoung Park2
  • Hyung-Su Kim2
  • Ji Hye Kim3
  • Jae Youl Cho3
  1. 1Department of Interdisciplinary Programs in Biocosmetics, Sungkyunkwan University, Suwon 16419 Suwon 16419 Republic of Korea
  2. 2Research and Innovation Center, AMOREPACIFIC, Yongin 17074 Suwon 16419 Republic of Korea
  3. 3Department of Integrative Biotechnology, Sungkyunkwan University Suwon 16419 Republic of Korea
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{yoon2026nrf2,
  title = {{Nrf2 Activation Induces Fibroblast Senescence and Promotes Melanosome Accumulation in a Fibroblast-Keratinocyte Co-Culture Model}},
  author = {Ji Hye Yoon and In Seop Kil and Siyoung Cho and Sunyoung Park and Hyung-Su Kim and Ji Hye Kim and Jae Youl Cho},
  journal = {Biomolecules \& Therapeutics},
  year = {2026},
  month = nov,
  doi = {10.4062/biomolther.2026.104},
  url = {https://doi.org/10.4062/biomolther.2026.104},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - Nrf2 Activation Induces Fibroblast Senescence and Promotes Melanosome Accumulation in a Fibroblast-Keratinocyte Co-Culture Model
AU  - Ji Hye Yoon
AU  - In Seop Kil
AU  - Siyoung Cho
AU  - Sunyoung Park
AU  - Hyung-Su Kim
AU  - Ji Hye Kim
AU  - Jae Youl Cho
PY  - 2026
DA  - 2026/11/01
JO  - Biomolecules & Therapeutics
DO  - 10.4062/biomolther.2026.104
UR  - https://doi.org/10.4062/biomolther.2026.104
AB  - 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.
SN  - 1976-9148
SN  - 2005-4483
ER  -