ArticleThe Journal of clinical investigation2016
Oxidative stress and dysfunctional NRF2 underlie pachyonychia congenita phenotypes.
Article in The Journal of clinical investigation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
32 citing papers in PubMed, 55 citations in OpenAlex.
- Failed metabolic adaptation to stress contributes to epidermal cell adhesion defects in Darier disease.Science advances · 2026Article
- Sulforaphane in Cutaneous Disorders and Skin Injury: Mechanisms, Evidence, and Clinical Perspectives.Nutrients · 2026Review
- Pachyonychia Congenita: A Research Agenda Leading to New Therapeutic Approaches.The Journal of investigative dermatology · 2024Review
- Treatment of palmoplantar keratoderma in a patient with ichthyosis with topical tapinarof.JAAD case reports · 2024Article
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- Vascular Endothelial Growth Factor A VEGFA Inhibition: An Effective Treatment Strategy for Psoriasis.International journal of molecular sciences · 2023Review
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- Role of Phytochemicals in Skin PhotoprotectionFrontiers in pharmacology · 2022Review
- Genotype‒Structurotype‒Phenotype Correlations in Patients with Pachyonychia Congenita.The Journal of investigative dermatology · 2021Article
- Nagashima-Type Palmoplantar Keratosis: Clinical Characteristics, Genetic Characterization, and Clinical Management.BioMed research international · 2021Review
- Overview of the molecular determinants contributing to the expression of Psoriasis and Psoriatic Arthritis phenotypes.Journal of cellular and molecular medicine · 2020Review
- Therapeutic effects of CO-releaser/Nrf2 activator hybrids (HYCOs) in the treatment of skin wound, psoriasis and multiple sclerosis.Redox biology · 2020Article
- Non-Esterified Fatty Acid-Induced Reactive Oxygen Species Mediated Granulosa Cells Apoptosis Is Regulated by Nrf2/p53 Signaling Pathway.Antioxidants (Basel, Switzerland) · 2020Article
- Genetic activation of Nrf2 reduces cutaneous symptoms in a murine model of Netherton syndrome.Disease models & mechanisms · 2020Article
- A role for keratins in supporting mitochondrial organization and function in skin keratinocytes.Molecular biology of the cell · 2020Article
- Keratin 14-dependent disulfides regulate epidermal homeostasis and barrier function via 14-3-3σ and YAP1.eLife · 2020Article
- Pathophysiology of pachyonychia congenita-associated palmoplantar keratoderma: new insights into skin epithelial homeostasis and avenues for treatment.The British journal of dermatology · 2020Review
- Article
- Altered keratinocyte differentiation is an early driver of keratin mutation-based palmoplantar keratoderma.Human molecular genetics · 2019Article
- Intermediate filaments and IF-associated proteins: from cell architecture to cell proliferation.Proceedings of the Japan Academy. Series B, Physical and biological sciences · 2019Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
Palmoplantar keratoderma (PPK) are debilitating lesions that arise in individuals with pachyonychia congenita (PC) and feature upregulation of danger-associated molecular patterns and skin barrier regulators. The defining features of PC-associated PPK are reproduced in mice null for keratin 16 (Krt16), which is commonly mutated in PC patients. Here, we have shown that PPK onset is preceded by oxidative stress in footpad skin of Krt16-/- mice and correlates with an inability of keratinocytes to sustain nuclear factor erythroid-derived 2 related factor 2-dependent (NRF2-dependent) synthesis of the cellular antioxidant glutathione (GSH). Additionally, examination of plantar skin biopsies from individuals with PC confirmed the presence of high levels of hypophosphorylated NRF2 in lesional tissue. In Krt16-/- mice, genetic ablation of Nrf2 worsened spontaneous skin lesions and accelerated PPK development in footpad skin. Hypoactivity of NRF2 in Krt16-/- footpad skin correlated with decreased levels or activity of upstream NRF2 activators, including PKCδ, receptor for activated C kinase 1 (RACK1), and p21. Topical application of the NRF2 activator sulforaphane to the footpad of Krt16-/- mice prevented the development of PPK and normalized redox balance via regeneration of GSH from existing cellular pools. Together, these findings point to oxidative stress and dysfunctional NRF2 as contributors to PPK pathogenesis, identify K16 as a regulator of NRF2 activation, and suggest that pharmacological activation of NRF2 should be further explored for PC treatment.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.