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ResearchIn-Press PreviewDermatologyMetabolism Open Access | 10.1172/jci.insight.189177

Epidermal NAD+ deficiency induces IL-36-mediated skin inflammation and acanthosis

Taiki Seki,1 Jun-Dal Kim,2 Yasuhito Yahara,1 Hitoshi Uchida,1 Keisuke Yaku,1 Mariam Karim,1 Teruhiko Makino,2 Tadamichi Shimizu,2 and Takashi Nakagawa1

1Department of Molecular and Medical Pharmacology, University of Toyama, Toyama, Japan

2Division of Complex Biosystem Research, University of Toyama, Toyama, Japan

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1Department of Molecular and Medical Pharmacology, University of Toyama, Toyama, Japan

2Division of Complex Biosystem Research, University of Toyama, Toyama, Japan

Find articles by Kim, J. in: PubMed | Google Scholar

1Department of Molecular and Medical Pharmacology, University of Toyama, Toyama, Japan

2Division of Complex Biosystem Research, University of Toyama, Toyama, Japan

Find articles by Yahara, Y. in: PubMed | Google Scholar

1Department of Molecular and Medical Pharmacology, University of Toyama, Toyama, Japan

2Division of Complex Biosystem Research, University of Toyama, Toyama, Japan

Find articles by Uchida, H. in: PubMed | Google Scholar

1Department of Molecular and Medical Pharmacology, University of Toyama, Toyama, Japan

2Division of Complex Biosystem Research, University of Toyama, Toyama, Japan

Find articles by Yaku, K. in: PubMed | Google Scholar

1Department of Molecular and Medical Pharmacology, University of Toyama, Toyama, Japan

2Division of Complex Biosystem Research, University of Toyama, Toyama, Japan

Find articles by Karim, M. in: PubMed | Google Scholar

1Department of Molecular and Medical Pharmacology, University of Toyama, Toyama, Japan

2Division of Complex Biosystem Research, University of Toyama, Toyama, Japan

Find articles by Makino, T. in: PubMed | Google Scholar

1Department of Molecular and Medical Pharmacology, University of Toyama, Toyama, Japan

2Division of Complex Biosystem Research, University of Toyama, Toyama, Japan

Find articles by Shimizu, T. in: PubMed | Google Scholar |

1Department of Molecular and Medical Pharmacology, University of Toyama, Toyama, Japan

2Division of Complex Biosystem Research, University of Toyama, Toyama, Japan

Find articles by Nakagawa, T. in: PubMed | Google Scholar |

Published February 10, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.189177.
Copyright © 2026, Seki et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 10, 2026 - Version history
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Abstract

Nicotinamide adenine dinucleotide (NAD⁺) is essential for cellular metabolism, DNA repair, and stress responses. NAD+ is synthesized from nicotinamide, nicotinic acid (collectively termed niacin), and tryptophan. In humans, deficiencies in these nutrients result in pellagra, marked by dermatitis, diarrhea, and dementia. The dermatitis associated with pellagra typically manifests as photodermatosis in sun-exposed areas. This study examined the effects of NAD+ deficiency on skin homeostasis using epidermis-specific Nampt conditional knockout (cKO) mice. These mice displayed substantial NAD⁺ depletion, reduced poly(ADP-ribose) polymerase (PARP) activity, and increased DNA damage. Consequently, Nampt cKO mice developed spontaneous skin inflammation and epidermal hyperplasia. RNA sequencing and immunohistochemical analyses demonstrated increased interleukin-36 (IL-36) cytokine expression, suggesting that DNA repair-related genomic stress triggers keratinocyte-driven IL-36 production, which promotes inflammation. Furthermore, reduced collagen17A1 expression and elevated thymic stromal lymphopoietin (TSLP) levels were observed. NAD+ repletion by transdermal supplementation of nicotinamide mononucleotide (NMN) suppressed the rise of IL-36 levels and skin inflammation. These findings underscore the importance of Nampt-mediated NAD⁺ metabolism for epidermal stability and indicate that NAD⁺ depletion may contribute to IL-36-mediated skin inflammation, offering insights for therapeutic strategies in inflammatory skin disorders.

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Version history
  • Version 1 (February 10, 2026): In-Press Preview
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