2026-10-30 九州大学
糖質コルチコイド過剰によりACTHが低下すると、ACTH-MC2R(メラノコルチン2受容体)の下流シグナルであるcAMP(環状アデノシン一リン酸)/PKA(プロテインキナーゼA)経路が抑制され、SF1/NRF2経路を介した抗酸化機能が弱まります。その結果、ミトコンドリアにROSが蓄積し、ミトコンドリア障害と副腎皮質束状層の細胞死が進みます。マウスではACTHまたは抗酸化物質であるNACがこれらの変化を軽減しました。
＜関連情報＞
- https://www.kyushu-u.ac.jp/ja/researches/view/1595
- https://www.nature.com/articles/s41419-026-09306-8
ACTH-SF1/NR5A1-NRF2軸がミトコンドリアROS蓄積を介してグルココルチコイド誘発性副腎皮質細胞死に果たす役割 Role of the ACTH-SF1/NR5A1-NRF2 axis in glucocorticoid-induced adrenocortical cell death through mitochondrial ROS accumulation
Naohiro Uchida, Namiko Kawamura, Hironobu Umakoshi, Maki Yokomoto-Umakoshi, Tazuru Fukumoto, Norifusa Iwahashi, Masamichi Fujita, Aya Fujimoto, Kaede Saito, Yuta Hiraike, Fumiya Takahashi, Takashi Baba, Masahide Seki, Yutaka Suzuki & Yoshihiro Ogawa
Cell Death & Disease Published:29 October 2026
DOI:https://doi.org/10.1038/s41419-026-09306-8
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.
