{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:50:49Z","timestamp":1791859849050,"version":"4.3.4"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T00:00:00Z","timestamp":1701302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["CRC\/Transregio 205\/1"],"award-info":[{"award-number":["CRC\/Transregio 205\/1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>We performed a transcriptomic analysis of adrenal signaling pathways in various forms of endogenous Cushing\u2019s syndrome (CS) to define areas of dysregulated and druggable targets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methodology<\/jats:title><jats:p>Next-generation sequencing was performed on adrenal samples of patients with primary bilateral macronodular adrenal hyperplasia (PBMAH, n=10) and control adrenal samples (n=8). The validation groups included cortisol-producing adenoma (CPA, n=9) and samples from patients undergoing bilateral adrenalectomy for Cushing\u2019s disease (BADX-CD, n=8). <jats:italic>In vivo<\/jats:italic> findings were further characterized using three adrenocortical cell-lines (NCI-H295R, CU-ACC2, MUC1).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Pathway mapping based on significant expression patterns identified PPARG (peroxisome proliferator-activated receptor gamma) pathway as the top hit. Quantitative PCR (QPCR) confirmed that <jats:italic>PPARG<\/jats:italic> (l2fc&amp;lt;-1.5) and related genes \u2013 <jats:italic>FABP4<\/jats:italic> (l2fc&amp;lt;-5.5), <jats:italic>PLIN1<\/jats:italic> (l2fc&amp;lt;-4.1) and <jats:italic>ADIPOQ<\/jats:italic> (l2fc&amp;lt;-3.3) \u2013 were significantly downregulated (p&amp;lt;0.005) in PBMAH. Significant downregulation of <jats:italic>PPARG<\/jats:italic> was also found in BADX-CD (l2fc&amp;lt;-1.9, p&amp;lt;0.0001) and CPA (l2fc&amp;lt;-1.4, p&amp;lt;0.0001). <jats:italic>In vitro<\/jats:italic> studies demonstrated that the PPARG activator rosiglitazone resulted in decreased cell viability in MUC1 and NCI-H295R (p&amp;lt;0.0001). There was also a significant reduction in the production of aldosterone, cortisol, and cortisone in NCI-H295R and in Dihydrotestosterone (DHT) in MUC1 (p&amp;lt;0.05), respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Outcome<\/jats:title><jats:p>This therapeutic effect was independent of the actions of ACTH, postulating a promising application of <jats:italic>PPARG<\/jats:italic> activation in endogenous hypercortisolism.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2023.1265794","type":"journal-article","created":{"date-parts":[[2023,12,1]],"date-time":"2023-12-01T09:22:51Z","timestamp":1701422571000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["PPARG dysregulation as a potential molecular target in adrenal Cushing's 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