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Testicular receptor 4 (TR4) has been identified as a novel drug target to treat Cushing's disease. We built the structure model of TR4 and searched the TR4 antagonist candidate via in silico virtual screening. Bexarotene was identified as an antagonist of TR4 that can directly interact with TR4 ligand binding domain (TR4\u2010LBD) and induces a conformational change in the secondary structure of TR4\u2010LBD. Bexarotene suppressed AtT\u201020 cell growth, proopiomelanocortin (POMC) expression and adrenocorticotropin (ACTH) secretion. Mechanism dissection revealed that bexarotene could suppress TR4\u2010increased POMC expression <jats:italic>via<\/jats:italic> promoting the TR4 translocation from the nucleus to the cytoplasm. This TR4 translocation might then result in reducing the TR4 binding to the TR4 response element (TR4RE) on the 5\u2019 promoter region of POMC. Results from in vivo mouse model also revealed that oral bexarotene administration markedly suppressed ACTH\u2010secreting tumour growth, adrenal enlargement and the secretion of ACTH and corticosterone in mice with already established tumours. Together, these results suggest that bexarotene may be developed as a potential novel therapeutic drug to better suppress Cushing's disease.<\/jats:p>","DOI":"10.1111\/jcmm.16074","type":"journal-article","created":{"date-parts":[[2021,1,25]],"date-time":"2021-01-25T05:12:56Z","timestamp":1611551576000},"page":"2404-2417","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Targeting the TR4 nuclear receptor with antagonist bexarotene can suppress the proopiomelanocortin signalling in AtT\u201020 cells"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5040-4992","authenticated-orcid":false,"given":"Liqun","family":"Xia","sequence":"first","affiliation":[{"name":"Department of Urology Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou 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