British journal of pharmacology · 2026
The β2-adrenoceptor agonist formoterol attenuates hallmarks of adrenal Cushing's syndrome.
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Cleveland Kristan H, Lee Kyung-Soon, Ponnalagu Devasena, Vicente Juan Jesus, Parker Edward D, Lee Ji Yae Eunice, Wordeman Linda, Scott John D
Аннотация
BACKGROUND AND PURPOSE: Signal transduction therapies aim to correct dysregulated cellular signalling pathways implicated in disease. Adrenal Cushing's syndrome, a disorder of excess cortisol production, is frequently driven by somatic mutations in protein kinase A catalytic subunits (PKAc), including PKAcL205R and PKAcW196R.
EXPERIMENTAL APPROACH: This study used a combination of in vitro adrenal cell models and an in vivo mouse model harbouring the PKAc W196R mutation to assess the effects of formoterol treatment on mitochondrial function, steroidogenic gene expression and cortisol production. Mitochondrial respiration was evaluated by Seahorse XF analysis and serial block face scanning electron microscopy, and protein expression was measured by western blot and immunohistochemistry.
KEY RESULTS: In this study, we demonstrate that the long-acting β2-adrenoceptor agonist formoterol can be repurposed to manage hypercortisolism. Formoterol significantly attenuates corticosterone secretion in ATC7L adrenal cells expressing Cushing's-associated PKAc variants. In a PKAcWT/W196R mouse model, formoterol treatment alleviates hypercortisolism without inducing adverse cardiovascular effects. Mechanistically, formoterol promotes nuclear translocation of PGC1α, leading to enhanced mitochondrial biogenesis and improved mitochondrial function, as confirmed by Seahorse metabolic analysis. Electron microscopy revealed increased mitochondrial number, volume and structural complexity in adrenal tissue. Analyses of patient samples and adrenal cell lines indicates that formoterol modulates the mitochondrial steroidogenic acute regulatory protein (StAR), suggesting a direct effect on steroidogenesis.
CONCLUSION AND IMPLICATIONS: These findings support the therapeutic potential of formoterol as a new pharmacological strategy for treating Cushing's syndrome and its associated metabolic comorbidities.
EXPERIMENTAL APPROACH: This study used a combination of in vitro adrenal cell models and an in vivo mouse model harbouring the PKAc W196R mutation to assess the effects of formoterol treatment on mitochondrial function, steroidogenic gene expression and cortisol production. Mitochondrial respiration was evaluated by Seahorse XF analysis and serial block face scanning electron microscopy, and protein expression was measured by western blot and immunohistochemistry.
KEY RESULTS: In this study, we demonstrate that the long-acting β2-adrenoceptor agonist formoterol can be repurposed to manage hypercortisolism. Formoterol significantly attenuates corticosterone secretion in ATC7L adrenal cells expressing Cushing's-associated PKAc variants. In a PKAcWT/W196R mouse model, formoterol treatment alleviates hypercortisolism without inducing adverse cardiovascular effects. Mechanistically, formoterol promotes nuclear translocation of PGC1α, leading to enhanced mitochondrial biogenesis and improved mitochondrial function, as confirmed by Seahorse metabolic analysis. Electron microscopy revealed increased mitochondrial number, volume and structural complexity in adrenal tissue. Analyses of patient samples and adrenal cell lines indicates that formoterol modulates the mitochondrial steroidogenic acute regulatory protein (StAR), suggesting a direct effect on steroidogenesis.
CONCLUSION AND IMPLICATIONS: These findings support the therapeutic potential of formoterol as a new pharmacological strategy for treating Cushing's syndrome and its associated metabolic comorbidities.