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Adrenal Cushing's syndrome, a disorder of excess cortisol production, is frequently driven by somatic mutations in protein kinase A catalytic subunits (PKAc), including PKAc\n                      <jats:sup>\n                        <jats:bold>L205R<\/jats:bold>\n                      <\/jats:sup>\n                      and PKAc\n                      <jats:sup>\n                        <jats:bold>W196R<\/jats:bold>\n                      <\/jats:sup>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      This study used a combination of\n                      <jats:italic>in vitro<\/jats:italic>\n                      adrenal cell models and an\n                      <jats:italic>in vivo<\/jats:italic>\n                      mouse model harbouring the\n                      <jats:italic>PKAc<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      In this study, we demonstrate that the long\u2010acting \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      \u2010adrenoceptor agonist formoterol can be repurposed to manage hypercortisolism. Formoterol significantly attenuates corticosterone secretion in ATC7L adrenal cells expressing Cushing's\u2010associated PKAc variants. In a PKAc\n                      <jats:sup>\n                        <jats:bold>WT\/W196R<\/jats:bold>\n                      <\/jats:sup>\n                      mouse model, formoterol treatment alleviates hypercortisolism without inducing adverse cardiovascular effects. Mechanistically, formoterol promotes nuclear translocation of PGC1\u03b1, 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>These findings support the therapeutic potential of formoterol as a new pharmacological strategy for treating Cushing's syndrome and its associated metabolic comorbidities.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70370","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T16:54:01Z","timestamp":1772988841000},"page":"3129-3145","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The \u03b2\n                    <sub>2<\/sub>\n                    \u2010adrenoceptor agonist formoterol attenuates hallmarks of adrenal Cushing's syndrome"],"prefix":"10.1111","volume":"183","author":[{"given":"Kristan H.","family":"Cleveland","sequence":"first","affiliation":[{"name":"Department of Pharmacology University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung\u2010Soon","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devasena","family":"Ponnalagu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Jesus","family":"Vicente","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Biophysics University of Washington  Seattle Washington 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