Skip to main content
ENDO 2026 Main banner

Adrenal (Excluding Mineralocorticoids)

SAT-448 - Role of the ACTH-SF1/NR5A1-NRF2 axis in glucocorticoid-induced adrenocortical cell death through mitochondrial ROS accumulation

Saturday, June 13, 2026
9:30 AM - 4:30 PM CT
Disclosure(s):
Masamichi Fujita, MD, PhD: No financial relationships to disclose
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 alteration in dexamethasone (DEX)-treated mice is similar to that 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 results in a nuclear factor E2-related factor 2 (NRF2)-dependent inhibition of 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 clue to a new therapeutic strategy to prevent or treat secondary adrenal insufficiency during glucocorticoid excess.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*