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Peer-reviewedCC BYCell death & disease

Role of the ACTH-SF1/NR5A1-NRF2 axis in glucocorticoid-induced adrenocortical cell death through mitochondrial ROS accumulation.

  • Naohiro Uchida1
  • Namiko Kawamura2
  • Hironobu Umakoshi1
  • Maki Yokomoto-Umakoshi1
  • Tazuru Fukumoto1
  • Norifusa Iwahashi1
  • Masamichi Fujita1
  • Aya Fujimoto1
  • Kaede Saito3
  • Yuta Hiraike3,4
  • Fumiya Takahashi5,6
  • Takashi Baba6,7
3 more authors
  • Masahide Seki8
  • Yutaka Suzuki8
  • Yoshihiro Ogawa9
9 affiliations
  1. 1Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  2. 2Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. [email protected].
  3. 3Division for Health Service Promotion, The University of Tokyo, Tokyo, Japan.
  4. 4Laboratory for Advanced Research on Pathophysiology of Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  5. 5Department of Anatomy, Kurume University School of Medicine, Kurume, Japan.
  6. 6Department of Molecular Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  7. 7Department of Systems Life Sciences, Graduate School of Systems Life Sciences, Kyushu University, Fukuoka, Japan.
  8. 8Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
  9. 9Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. [email protected].
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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.

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Cite

BibTeXRIS
BibTeX
@article{uchida2026role,
  title = {{Role of the ACTH-SF1/NR5A1-NRF2 axis in glucocorticoid-induced adrenocortical cell death through mitochondrial ROS accumulation.}},
  author = {Naohiro Uchida and Namiko Kawamura and Hironobu Umakoshi and Maki Yokomoto-Umakoshi and Tazuru Fukumoto and Norifusa Iwahashi and Masamichi Fujita and Aya Fujimoto and Kaede Saito and Yuta Hiraike and Fumiya Takahashi and Takashi Baba and Masahide Seki and Yutaka Suzuki and Yoshihiro Ogawa},
  journal = {Cell death \& disease},
  year = {2026},
  month = oct,
  doi = {10.1038/s41419-026-09306-8},
  url = {https://europepmc.org/article/MED/42957660},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Role of the ACTH-SF1/NR5A1-NRF2 axis in glucocorticoid-induced adrenocortical cell death through mitochondrial ROS accumulation.
AU  - Naohiro Uchida
AU  - Namiko Kawamura
AU  - Hironobu Umakoshi
AU  - Maki Yokomoto-Umakoshi
AU  - Tazuru Fukumoto
AU  - Norifusa Iwahashi
AU  - Masamichi Fujita
AU  - Aya Fujimoto
AU  - Kaede Saito
AU  - Yuta Hiraike
AU  - Fumiya Takahashi
AU  - Takashi Baba
AU  - Masahide Seki
AU  - Yutaka Suzuki
AU  - Yoshihiro Ogawa
PY  - 2026
DA  - 2026/10/29
JO  - Cell death & disease
DO  - 10.1038/s41419-026-09306-8
UR  - https://europepmc.org/article/MED/42957660
AB  - 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.
SN  - 2041-4889
ER  -