{
  "abstract": "Exogenous glucocorticoids are widely used to treat inflammatory and autoimmune diseases, yet the prolonged administration often leads to adrenocortical atrophy and subsequent adrenal insufficiency. However, the molecular mechanisms underlying glucocorticoid-induced adrenocortical atrophy remain incompletely understood. Here, we show that adrenocortical alterations in dexamethasone (DEX)-treated mice are similar to those in human adrenocortical tissues adjacent to cortisol-producing adenoma. During DEX treatment, marked cell death occurs, being restricted to the adrenocortical zona fasciculata (ZF), as a result of reactive oxygen species (ROS)-mediated mitochondrial dysfunction; the pathological changes are all attenuated by co-administration of adrenocorticotropic hormone (ACTH). In DEX-treated mice, ACTH deficiency impairs nuclear factor E2-related factor 2 (NRF2)-dependent redox homeostasis in ZF cells. Activation of the cAMP-PKA signaling pathway, a downstream signaling of ACTH stimulation, increases gene expression of steroidogenic factor 1 (SF1; NR5A1) in cultured adrenocortical cells in vitro, where it binds directly to the Nrf2 promoter and enhances its transcription, thereby promoting antioxidant gene expression to maintain redox homeostasis. This study highlights the role of the ACTH-SF1-NRF2 axis in glucocorticoid-induced adrenocortical cell death through mitochondrial ROS accumulation, thereby providing a clue to a new therapeutic strategy to prevent or treat secondary adrenal insufficiency during glucocorticoid excess.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.",
    "Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. kawamura.namiko.994@m.kyushu-u.ac.jp.",
    "Division for Health Service Promotion, The University of Tokyo, Tokyo, Japan.",
    "Laboratory for Advanced Research on Pathophysiology of Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.",
    "Department of Anatomy, Kurume University School of Medicine, Kurume, Japan.",
    "Department of Molecular Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.",
    "Department of Systems Life Sciences, Graduate School of Systems Life Sciences, Kyushu University, Fukuoka, Japan.",
    "Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.",
    "Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. yogawa@med.kyushu-u.ac.jp."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Naohiro Uchida",
      "orcid": "0000-0002-3820-7731"
    },
    {
      "affs": [
        1
      ],
      "name": "Namiko Kawamura",
      "orcid": "0000-0002-9206-2844"
    },
    {
      "affs": [
        0
      ],
      "name": "Hironobu Umakoshi",
      "orcid": "0000-0003-4293-287X"
    },
    {
      "affs": [
        0
      ],
      "name": "Maki Yokomoto-Umakoshi"
    },
    {
      "affs": [
        0
      ],
      "name": "Tazuru Fukumoto"
    },
    {
      "affs": [
        0
      ],
      "name": "Norifusa Iwahashi"
    },
    {
      "affs": [
        0
      ],
      "name": "Masamichi Fujita",
      "orcid": "0009-0008-1316-1774"
    },
    {
      "affs": [
        0
      ],
      "name": "Aya Fujimoto"
    },
    {
      "affs": [
        2
      ],
      "name": "Kaede Saito"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Yuta Hiraike"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Fumiya Takahashi"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Takashi Baba"
    },
    {
      "affs": [
        7
      ],
      "name": "Masahide Seki",
      "orcid": "0000-0001-6091-8698"
    },
    {
      "affs": [
        7
      ],
      "name": "Yutaka Suzuki"
    },
    {
      "affs": [
        8
      ],
      "name": "Yoshihiro Ogawa",
      "orcid": "0000-0002-0834-2836"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/e7zcxcgbax0tf.bib",
  "cited_by": 0,
  "doi": "10.1038/s41419-026-09306-8",
  "fulltext_url": "https://europepmc.org/articles/PMC13720010",
  "id": "e7zcxcgbax0tf",
  "issns": [
    "2041-4889"
  ],
  "landing_url": "https://europepmc.org/article/MED/42957660",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "2712|Adrenal Hormones and Disorders"
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  "openalex": "W7224169474",
  "pdf_url": "https://europepmc.org/articles/PMC13720010?pdf=render",
  "pmcid": "PMC13720010",
  "pmid": "42957660",
  "published": "2026-10-29",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/e7zcxcgbax0tf.ris",
  "sources": [
    {
      "first_seen": "2026-11-01T00:20:36Z",
      "native_id": "MED:42957660",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42957660"
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    {
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      "native_id": "PMC13720010",
      "source": "pmc",
      "url": "https://doi.org/10.1038/s41419-026-09306-8"
    }
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2712|Adrenal Hormones and Disorders",
      "subfield": "endocrinology-metabolism"
    }
  ],
  "title": "Role of the ACTH-SF1/NR5A1-NRF2 axis in glucocorticoid-induced adrenocortical cell death through mitochondrial ROS accumulation.",
  "title_text": "Role of the ACTH-SF1/NR5A1-NRF2 axis in glucocorticoid-induced adrenocortical cell death through mitochondrial ROS accumulation.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-03T12:20:58Z",
  "url": "https://research.draconitic.com/paper/e7zcxcgbax0tf",
  "venue": "Cell death & disease",
  "versions": []
}