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ResearchIn-Press PreviewDermatologyOncology Open Access | 10.1172/JCI189044

Inhibiting LSD1 unlocks retinoid AP-1 programming to activate epithelial immunity and skin tumor suppression

Nina Kuprasertkul,1 Alyssa F. Moore,1 Carina A. D'souza,1 Julia Chini,2 Eun-Kyung Ko,1 Sijia Huang,3 Shuo Zhang,4 Ashley S. Anderson,1 Shaun Egolf,1 Laura V. Pinheiro,5 Alison Jaccard,5 Claudia T. Magahis,1 Lydia Bao,1 Yann Aubert,1 Cyria R. Olingou,1 Stephen M. Prouty,1 Donna Brennan-Crispi,1 David A. Hill,6 John T. Seykora,1 Kathryn E. Wellen,5 and Brian C. Capell1

1Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Penn Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

4Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

6Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Kuprasertkul, N. in: PubMed | Google Scholar

1Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Penn Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

4Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

6Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Moore, A. in: PubMed | Google Scholar

1Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Penn Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

4Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

6Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by D'souza, C. in: PubMed | Google Scholar

1Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Penn Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

4Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

6Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, United States of America

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

1Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Penn Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

4Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

6Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Ko, E. in: PubMed | Google Scholar

1Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Penn Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

4Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

6Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Huang, S. in: PubMed | Google Scholar

1Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Penn Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

4Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

6Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Zhang, S. in: PubMed | Google Scholar

1Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Penn Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

4Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

6Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Anderson, A. in: PubMed | Google Scholar

1Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Penn Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

4Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

6Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Egolf, S. in: PubMed | Google Scholar |

1Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Penn Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

4Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

6Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Pinheiro, L. in: PubMed | Google Scholar

1Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Penn Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

4Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

6Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Jaccard, A. in: PubMed | Google Scholar

1Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Penn Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

4Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

6Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Magahis, C. in: PubMed | Google Scholar

1Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Penn Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

4Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

6Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Bao, L. in: PubMed | Google Scholar

1Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Penn Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

4Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

6Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, United States of America

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

1Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Penn Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

4Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

6Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Olingou, C. in: PubMed | Google Scholar

1Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Penn Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

4Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

6Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Prouty, S. in: PubMed | Google Scholar

1Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Penn Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

4Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

6Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Brennan-Crispi, D. in: PubMed | Google Scholar

1Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Penn Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

4Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

6Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Hill, D. in: PubMed | Google Scholar |

1Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Penn Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

4Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

6Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, United States of America

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

1Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Penn Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

4Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

6Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, United States of America

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

1Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Penn Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

4Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

6Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Capell, B. in: PubMed | Google Scholar

Published March 12, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI189044.
Copyright © 2026, Kuprasertkul 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 March 12, 2026 - Version history
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Abstract

Lysine-specific demethylase 1 (LSD1; KDM1A) orchestrates context-dependent chromatin programs, yet its role in epithelial immunity remains largely unknown. Here, we identify LSD1 as a central brake on retinoid- and AP-1–driven enhancer activation in epidermis and demonstrate that its inhibition induces anti-tumor immunity. While epidermal LSD1 is required during development, acute loss or topical inhibition in adult skin is tolerated and triggers coordinated expression of retinoic acid signaling, lipid remodeling, and chemokine induction pathways. CUT&RUN profiling reveals that LSD1 occupies enhancer regions enriched for AP-1 motifs at retinoid metabolism, lipid homeostasis, and immune genes. LSD1 loss increases H3K4me1/2 and gene activation at these sites, licensing a poised AP-1–retinoid program. Single-cell spatial analyses show that discrete keratinocyte subsets initiate retinoid signaling to recruit dendritic cells and activate CD4+ T cell responses. Topical LSD1 inhibition suppresses cutaneous squamous cell carcinoma in two models while amplifying keratinocyte–immune crosstalk. Functional perturbations reveal that retinoid signaling partially contributes, whereas CD4+ T cells are essential for tumor control. These findings define LSD1 as a master repressor of epithelial immune competence and nominate LSD1 inhibition as a therapeutic strategy to activate retinoid–AP-1 enhancer circuits and drive CD4-dependent tumor immunity in skin cancer.

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