{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T08:40:15Z","timestamp":1785400815263,"version":"3.56.0"},"reference-count":117,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32401009, 22407100"],"award-info":[{"award-number":["32401009, 22407100"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["32401009, 22407100"],"award-info":[{"award-number":["32401009, 22407100"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Shandong Provincial Postdoctoral Innovation Project","award":["SDCX-ZG-202502096"],"award-info":[{"award-number":["SDCX-ZG-202502096"]}]},{"DOI":"10.13039\/501100003787","name":"Hebei Natural Science Foundation","doi-asserted-by":"publisher","award":["B2025110005"],"award-info":[{"award-number":["B2025110005"]}],"id":[{"id":"10.13039\/501100003787","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Testicular receptor 4 (TR4, NR2C2) is an orphan nuclear receptor involved in the regulation of metabolism, inflammation, cardiovascular disease, and cancer. Accumulating evidence indicates that TR4 exhibits functional plasticity, exerting protective or pathogenic effects depending on tissue and disease context, and sometimes displaying opposing roles within the same disease. However, the mechanisms underlying this functional duality remain poorly understood. Recent studies indicate that TR4 activity is determined not only by the receptor itself but also by dynamic coregulatory networks. Through interactions with coactivators, corepressors, epigenetic regulators, and environmental signaling pathways, TR4 integrates metabolic cues to generate context-dependent transcriptional programs. Coactivator networks centered on PGC-1\u03b1, steroid receptor coactivator (SRC) family members, and CBP\/p300 support oxidative metabolism and anti-inflammatory responses, whereas RIP140-, NCoR\/SMRT-, and HDAC-associated networks promote lipid accumulation, chronic inflammation, fibrosis, and tumor progression. Regulators such as JAZF1 further influence TR4 activity by reshaping coregulator recruitment and target-gene selection. In this review, we summarize the structural basis of TR4 regulation and discuss how coregulatory network remodeling governs its functions in metabolic, cardiovascular, inflammatory, and malignant diseases. We propose that TR4 functions as a context-dependent transcriptional platform whose activities are defined by its coregulatory landscape, providing a framework for precision therapies.<\/jats:p>","DOI":"10.3390\/cells15131218","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T16:15:53Z","timestamp":1783095353000},"page":"1218","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Coregulatory Networks Remodel the Disease-Specific Functions of Orphan Nuclear Receptor TR4"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0185-9293","authenticated-orcid":false,"given":"Yunlong","family":"Liu","sequence":"first","affiliation":[{"name":"School of Life Sciences, Tiangong University, Tianjin 300387, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5509-7145","authenticated-orcid":false,"given":"Qing","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Tiangong University, Tianjin 300387, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyuan","family":"Cheng","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Tiangong University, Tianjin 300387, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6966-5146","authenticated-orcid":false,"given":"Mengtian","family":"Ren","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Tiangong University, Tianjin 300387, China"},{"name":"Cangzhou Institute of Tiangong University, Cangzhou 061000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8699-9518","authenticated-orcid":false,"given":"Xiuping","family":"Fu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Tiangong University, Tianjin 300387, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/bs.pmbts.2022.07.014","article-title":"Nuclear receptor: Structure and function,, Progress in molecular biology and translational science","volume":"196","author":"Sar","year":"2023","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"112653","DOI":"10.1016\/j.cellsig.2026.112653","article-title":"Orphan nuclear receptors: Structural mechanisms, ligand discovery, and therapeutic potential","volume":"146","author":"Liu","year":"2026","journal-title":"Cell. Signal."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1210\/me.2013-1422","article-title":"Minireview: Pathophysiological roles of the TR4 nuclear receptor: Lessons learned from mice lacking TR4","volume":"28","author":"Lin","year":"2014","journal-title":"Mol. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/bs.ctdb.2017.02.002","article-title":"TR2 and TR4 Orphan Nuclear Receptors: An Overview","volume":"125","author":"Lin","year":"2017","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.biochi.2016.04.012","article-title":"MiRNA-133a attenuates lipid accumulation via TR4-CD36 pathway in macrophages","volume":"127","author":"Peng","year":"2016","journal-title":"Biochimie"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1210\/me.2010-0455","article-title":"Mice lacking TR4 nuclear receptor develop mitochondrial myopathy with deficiency in complex I","volume":"25","author":"Liu","year":"2011","journal-title":"Mol. Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.3389\/fimmu.2020.01848","article-title":"Differential Host Pro-Inflammatory Response to Mycobacterial Cell Wall Lipids Regulated by the Mce1 Operon","volume":"11","author":"Petrilli","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"78","DOI":"10.3389\/fendo.2015.00078","article-title":"TR4 Nuclear Receptor Different Roles in Prostate Cancer Progression","volume":"6","author":"Lin","year":"2015","journal-title":"Front. Endocrinol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"R279","DOI":"10.1530\/ERC-13-0529","article-title":"Differential roles of PPAR\u03b3 vs. TR4 in prostate cancer and metabolic diseases","volume":"21","author":"Liu","year":"2014","journal-title":"Endocr.-Relat. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/j.bbrc.2017.06.057","article-title":"Sirtuin 7-dependent deacetylation of DDB1 regulates the expression of nuclear receptor TR4","volume":"490","author":"Karim","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"100775","DOI":"10.1016\/j.aohep.2022.100775","article-title":"Testicular orphan receptor 4 induced hepatic stellate cells activation via the regulation of TGF-\u03b2 receptor I\/Smad2\/3 signaling pathway","volume":"28","author":"Fu","year":"2023","journal-title":"Ann. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/s41419-018-0287-5","article-title":"TR(4) nuclear receptor suppresses HCC cell invasion via downregulating the EphA2 expression","volume":"9","author":"Jin","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"32088","DOI":"10.18632\/oncotarget.8525","article-title":"TR4 nuclear receptor enhances the cisplatin chemo-sensitivity via altering the ATF3 expression to better suppress HCC cell growth","volume":"7","author":"Shen","year":"2016","journal-title":"Oncotarget"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"21129","DOI":"10.1074\/jbc.M110.208181","article-title":"Increased acetylation in the DNA-binding domain of TR4 nuclear receptor by the coregulator ARA55 leads to suppression of TR4 transactivation","volume":"286","author":"Xie","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Liu, Y., Yang, H., Ren, M., Yu, Q., Xu, Q., and Fu, X. (2025). Orphan nuclear receptors TR2 and TR4 in erythropoiesis: From mechanisms to therapies. Biomolecules, 15.","DOI":"10.3390\/biom15060798"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/S0960-0760(02)00118-8","article-title":"Recent advances in the TR2 and TR4 orphan receptors of the nuclear receptor superfamily","volume":"81","author":"Lee","year":"2002","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Myers, G., Sun, Y., Wang, Y., Benmhammed, H., and Cui, S. (2024). Roles of Nuclear Orphan Receptors TR2 and TR4 during Hematopoiesis. Genes, 15.","DOI":"10.3390\/genes15050563"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1186\/s13578-020-00482-4","article-title":"Beta-catenin inhibits TR4-mediated lipid accumulation in 3T3-L1 adipocytes via induction of Slug","volume":"10","author":"Choi","year":"2020","journal-title":"Cell Biosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1074\/jbc.C100631200","article-title":"Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta), a novel PGC-1-related transcription coactivator associated with host cell factor","volume":"277","author":"Lin","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1093\/nar\/gkac1259","article-title":"Structures of human TR4LBD-JAZF1 and TR4DBD-DNA complexes reveal the molecular basis of transcriptional regulation","volume":"51","author":"Liu","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.mce.2004.07.001","article-title":"Molecular interaction of retinoic acid receptors with coregulators PCAF and RIP140","volume":"226","author":"Chen","year":"2004","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2072","DOI":"10.1074\/mcp.M600180-MCP200","article-title":"Modulation of testicular receptor 4 activity by mitogen-activated protein kinase-mediated phosphorylation","volume":"5","author":"Huq","year":"2006","journal-title":"Mol. Cell Proteom."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4194","DOI":"10.1093\/nar\/gkh741","article-title":"TIP27: A novel repressor of the nuclear orphan receptor TAK1\/TR4","volume":"32","author":"Nakajima","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1002\/ijc.31289","article-title":"Preclinical studies using miR-32-5p to suppress clear cell renal cell carcinoma metastasis via altering the miR-32-5p\/TR4\/HGF\/Met signaling","volume":"143","author":"Wang","year":"2018","journal-title":"Int. J. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2832","DOI":"10.1101\/gad.1593307","article-title":"The TR2 and TR4 orphan nuclear receptors repress Gata1 transcription","volume":"21","author":"Tanabe","year":"2007","journal-title":"Genes Dev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2877","DOI":"10.1074\/jbc.M110.168740","article-title":"The orphan nuclear receptor TR4 is a vitamin A-activated nuclear receptor","volume":"286","author":"Zhou","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1016\/j.ijpara.2006.06.003","article-title":"SmTR2\/4, a Schistosoma mansoni homologue of TR2\/TR4 orphan nuclear receptor","volume":"36","author":"Hu","year":"2006","journal-title":"Int. J. Parasitol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.bbrc.2006.10.021","article-title":"Transactivation of the proximal promoter of human oxytocin gene by TR4 orphan receptor","volume":"351","author":"Wang","year":"2006","journal-title":"Biochem Biophys. Res. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.bbrc.2004.12.146","article-title":"Induction of apolipoprotein E expression by TR4 orphan nuclear receptor via 5\u2032 proximal promoter region","volume":"328","author":"Kim","year":"2005","journal-title":"Biochem Biophys. Res. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1111\/j.1872-034X.2007.00208.x","article-title":"Collective repression of the hepatitis B virus enhancer II by human TR4 and TR2 orphan receptors","volume":"38","author":"Lin","year":"2008","journal-title":"Hepatol. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3444","DOI":"10.1038\/s44318-026-00760-w","article-title":"Orphan nuclear receptors recruit TRIM28 to promote telomeric H3K9me3 for the ALT pathway","volume":"45","author":"Tsai","year":"2026","journal-title":"EMBO J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/S0960-0760(03)00230-9","article-title":"Dual mechanisms of regulation of transcription of luteinizing hormone receptor gene by nuclear orphan receptors and histone deacetylase complexes","volume":"85","author":"Zhang","year":"2003","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1016\/j.bbagrm.2009.09.010","article-title":"Activation of testicular orphan receptor 4 by fatty acids","volume":"1789","author":"Tsai","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"13353","DOI":"10.1073\/pnas.0905724106","article-title":"TR4 nuclear receptor functions as a fatty acid sensor to modulate CD36 expression and foam cell formation","volume":"106","author":"Xie","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/S0092-8674(00)81410-5","article-title":"A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis","volume":"92","author":"Puigserver","year":"1998","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1128\/MCB.00247-14","article-title":"PGC-1 coactivator activity is required for murine erythropoiesis","volume":"34","author":"Cui","year":"2014","journal-title":"Mol. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/42750","article-title":"A signature motif in transcriptional co-activators mediates binding to nuclear receptors","volume":"387","author":"Heery","year":"1997","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1126\/science.270.5240.1354","article-title":"Sequence and characterization of a coactivator for the steroid hormone receptor superfamily","volume":"270","author":"Tsai","year":"1995","journal-title":"Science"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1038\/365855a0","article-title":"Phosphorylated CREB binds specifically to the nuclear protein CBP","volume":"365","author":"Chrivia","year":"1993","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S0092-8674(00)81118-6","article-title":"A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors","volume":"85","author":"Kamei","year":"1996","journal-title":"Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"10626","DOI":"10.1073\/pnas.93.20.10626","article-title":"The nuclear hormone receptor coactivator SRC-1 is a specific target of p300","volume":"93","author":"Yao","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1038\/382319a0","article-title":"A p300\/CBP-associated factor that competes with the adenoviral oncoprotein E1A","volume":"382","author":"Yang","year":"1996","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1101\/gad.12.11.1638","article-title":"The histone acetylase PCAF is a nuclear receptor coactivator","volume":"12","author":"Blanco","year":"1998","journal-title":"Genes Dev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.bbrc.2007.06.168","article-title":"TR4 orphan nuclear receptor functions as an apoptosis modulator via regulation of Bcl-2 gene expression","volume":"361","author":"Kim","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6745","DOI":"10.1128\/MCB.18.11.6745","article-title":"Cloning and characterization of mouse RIP140, a corepressor for nuclear orphan receptor TR2","volume":"18","author":"Lee","year":"1998","journal-title":"Mol. Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1074\/mcp.M500236-MCP200","article-title":"Regulation of co-repressive activity of and HDAC recruitment to RIP140 by site-specific phosphorylation","volume":"4","author":"Gupta","year":"2005","journal-title":"Mol. Cell Proteom."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1210\/mend.12.6.0123","article-title":"A regulatory role for RIP140 in nuclear receptor activation","volume":"12","author":"Treuter","year":"1998","journal-title":"Mol. Endocrinol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"16107","DOI":"10.1074\/jbc.M010185200","article-title":"Ligand-dependent formation of retinoid receptors, receptor-interacting protein 140 (RIP140), and histone deacetylase complex is mediated by a novel receptor-interacting motif of RIP140","volume":"276","author":"Wei","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"9383","DOI":"10.1128\/MCB.25.21.9383-9391.2005","article-title":"RIP140-targeted repression of gene expression in adipocytes","volume":"25","author":"Christian","year":"2005","journal-title":"Mol. Cell Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"8437","DOI":"10.1073\/pnas.0401013101","article-title":"Nuclear receptor corepressor RIP140 regulates fat accumulation","volume":"101","author":"Leonardsson","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/377397a0","article-title":"Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor","volume":"377","author":"Heinzel","year":"1995","journal-title":"Nature"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/377454a0","article-title":"A transcriptional co-repressor that interacts with nuclear hormone receptors","volume":"377","author":"Chen","year":"1995","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/S0092-8674(00)80218-4","article-title":"Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase","volume":"89","author":"Nagy","year":"1997","journal-title":"Cell"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1101\/gad.14.9.1048","article-title":"A core SMRT corepressor complex containing HDAC3 and TBL1, a WD40-repeat protein linked to deafness","volume":"14","author":"Guenther","year":"2000","journal-title":"Genes Dev."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/S1097-2765(02)00468-9","article-title":"The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2","volume":"9","author":"Zhang","year":"2002","journal-title":"Mol. Cell"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1038\/nm.2744","article-title":"Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration","volume":"18","author":"Sun","year":"2012","journal-title":"Nat. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.1016\/j.gendis.2022.10.029","article-title":"New insights into the suppression of inflammation and lipid accumulation by JAZF1","volume":"10","author":"Chen","year":"2023","journal-title":"Genes Dis."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"847","DOI":"10.3892\/or.2021.7925","article-title":"Use of miR-145 and testicular nuclear receptor 4 inhibition to reduce chemoresistance to docetaxel in prostate cancer","volume":"45","author":"Zhu","year":"2021","journal-title":"Oncol. Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1111\/1748-5967.12217","article-title":"Pyriproxyfen inhibits the suppressive effect of inflammatory signal on TR4 activity","volume":"47","author":"Choi","year":"2017","journal-title":"Entomol. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1186\/s40001-024-01742-6","article-title":"TR4 worsen urosepsis by regulating GSDMD","volume":"29","author":"Wang","year":"2024","journal-title":"Eur. J. Med. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.cell.2004.09.013","article-title":"Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice","volume":"119","author":"Lin","year":"2004","journal-title":"Cell"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"6695","DOI":"10.1074\/jbc.M009404200","article-title":"Core LXXLL motif sequences in CREB-binding protein, SRC1, and RIP140 define affinity and selectivity for steroid and retinoid receptors","volume":"276","author":"Heery","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"7976","DOI":"10.1158\/0008-5472.CAN-04-4076","article-title":"SRC-3 is required for prostate cancer cell proliferation and survival","volume":"65","author":"Zhou","year":"2005","journal-title":"Cancer Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"10594","DOI":"10.1158\/0008-5472.CAN-06-1023","article-title":"Androgens modulate expression of transcription intermediary factor 2, an androgen receptor coactivator whose expression level correlates with early biochemical recurrence in prostate cancer","volume":"66","author":"Agoulnik","year":"2006","journal-title":"Cancer Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1158\/1535-7163.MCT-14-0971","article-title":"TR4 Nuclear Receptor Alters the Prostate Cancer CD133+ Stem\/Progenitor Cell Invasion via Modulating the EZH2-Related Metastasis Gene Expression","volume":"14","author":"Zhu","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.mce.2011.08.033","article-title":"Nuclear hormone receptor co-repressors: Structure and function","volume":"348","author":"Watson","year":"2012","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.ccr.2010.10.022","article-title":"Hdac3 is essential for the maintenance of chromatin structure and genome stability","volume":"18","author":"Bhaskara","year":"2010","journal-title":"Cancer Cell"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.bbrc.2013.12.094","article-title":"Overexpression of Jazf1 reduces body weight gain and regulates lipid metabolism in high fat diet","volume":"444","author":"Jang","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1038\/ng.120","article-title":"Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes","volume":"40","author":"Zeggini","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"177","DOI":"10.2337\/db10-0628","article-title":"Nuclear orphan receptor TAK1\/TR4-deficient mice are protected against obesity-linked inflammation, hepatic steatosis, and insulin resistance","volume":"60","author":"Kang","year":"2011","journal-title":"Diabetes"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1550762919899643","DOI":"10.1177\/1550762919899643","article-title":"Using Chromatin-Nuclear Receptor Interactions to Quantitate Endocrine, Paracrine, and Autocrine Signaling","volume":"17","author":"Taves","year":"2020","journal-title":"Nucl. Recept. Signal."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/978-1-4939-1346-6_3","article-title":"Analysis of chromatin-nuclear receptor interactions by laser-chromatin immunoprecipitation","volume":"1204","author":"Benedetti","year":"2014","journal-title":"Steroid Receptors: Methods and Protocols"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2901","DOI":"10.2337\/db07-0359","article-title":"Loss of TR4 orphan nuclear receptor reduces phosphoenolpyruvate carboxykinase-mediated gluconeogenesis","volume":"56","author":"Liu","year":"2007","journal-title":"Diabetes"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.2337\/db10-0393","article-title":"Metformin inhibits nuclear receptor TR4-mediated hepatic stearoyl-CoA desaturase 1 gene expression with altered insulin sensitivity","volume":"60","author":"Kim","year":"2011","journal-title":"Diabetes"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2763","DOI":"10.1016\/j.febslet.2011.08.002","article-title":"TR4 activates FATP1 gene expression to promote lipid accumulation in 3T3-L1 adipocytes","volume":"585","author":"Choi","year":"2011","journal-title":"FEBS Lett."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"3947","DOI":"10.1016\/j.febslet.2014.09.007","article-title":"TR4 promotes fatty acid synthesis in 3T3-L1 adipocytes by activation of pyruvate carboxylase expression","volume":"588","author":"Park","year":"2014","journal-title":"FEBS Lett."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2220","DOI":"10.1007\/s001250100032","article-title":"Mutation analysis of peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) and relationships of identified amino acid polymorphisms to Type II diabetes mellitus","volume":"44","author":"Ek","year":"2001","journal-title":"Diabetologia"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Ho, M.M., Yoganathan, P., Chu, K.Y., Karunakaran, S., Johnson, J.D., and Clee, S.M. (2013). Diabetes genes identified by genome-wide association studies are regulated in mice by nutritional factors in metabolically relevant tissues and by glucose concentrations in islets. BMC Genet., 14.","DOI":"10.1186\/1471-2156-14-10"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2687","DOI":"10.1210\/me.2007-0213","article-title":"The nuclear receptor cofactor, receptor-interacting protein 140, is required for the regulation of hepatic lipid and glucose metabolism by liver X receptor","volume":"21","author":"Herzog","year":"2007","journal-title":"Mol. Endocrinol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1093\/carcin\/bgu052","article-title":"TR4 nuclear receptor functions as a tumor suppressor for prostate tumorigenesis via modulation of DNA damage\/repair system","volume":"35","author":"Lin","year":"2014","journal-title":"Carcinogenesis"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.lungcan.2015.06.007","article-title":"Testicular orphan receptor 4 (TR4) is a marker for metastasis and poor prognosis in non-small cell lung cancer that drives the EMT phenotype","volume":"89","author":"Zhang","year":"2015","journal-title":"Lung Cancer"},{"key":"ref_82","first-page":"17","article-title":"Cancer statistics, 2023","volume":"73","author":"Siegel","year":"2023","journal-title":"CA Cancer J. Clin."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41572-020-00243-0","article-title":"Prostate cancer","volume":"7","author":"Rebello","year":"2021","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"5965","DOI":"10.1158\/0008-5472.CAN-06-3168","article-title":"Genetic ablation of the amplified-in-breast cancer 1 inhibits spontaneous prostate cancer progression in mice","volume":"67","author":"Chung","year":"2007","journal-title":"Cancer Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"755","DOI":"10.18632\/oncotarget.23146","article-title":"Jazf1 promotes prostate cancer progression by activating JNK\/Slug","volume":"9","author":"Sung","year":"2018","journal-title":"Oncotarget"},{"key":"ref_86","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1038\/s41388-023-02665-y","article-title":"Hypoxia-responsive PPARGC1A\/BAMBI\/ACSL5 axis promotes progression and resistance to lenvatinib in hepatocellular carcinoma","volume":"42","author":"Zhang","year":"2023","journal-title":"Oncogene"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1002\/hep.31280","article-title":"PPAR\u03b3 Coactivator-1\u03b1 Suppresses Metastasis of Hepatocellular Carcinoma by Inhibiting Warburg Effect by PPAR\u03b3-Dependent WNT\/\u03b2-Catenin\/Pyruvate Dehydrogenase Kinase Isozyme 1 Axis","volume":"73","author":"Zuo","year":"2021","journal-title":"Hepatology"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Wang, X., Liao, Z., Bai, Z., He, Y., Duan, J., and Wei, L. (2018). MiR-93-5p Promotes Cell Proliferation through Down-Regulating PPARGC1A in Hepatocellular Carcinoma Cells by Bioinformatics Analysis and Experimental Verification. Genes, 9.","DOI":"10.3390\/genes9010051"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"46919","DOI":"10.1074\/jbc.M304088200","article-title":"Disruption of TR4 orphan nuclear receptor reduces the expression of liver apolipoprotein E\/C-I\/C-II gene cluster","volume":"278","author":"Kim","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_91","first-page":"3854041","article-title":"Tr4 Nuclear Receptor Suppresses Hepatocellular Carcinoma Metastasis via Altering the Mir-892c-3p\/Timp2 Signals","volume":"35","author":"Luo","year":"2021","journal-title":"SSRN Electron. J."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1038\/nrc2695","article-title":"Normal and cancer-related functions of the p160 steroid receptor co-activator (SRC) family","volume":"9","author":"Xu","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1038\/nm.4070","article-title":"ROR-\u03b3 drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer","volume":"22","author":"Wang","year":"2016","journal-title":"Nat. Med."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Shen, L., Zheng, J., Baur, G., Yasen, D., Zhu, H., Li, Y.-N., Meng, X., Trinh-Minh, T., and Filla, T. (2026). The nuclear receptor testicular receptor 4 orchestrates cytoskeletal organization in a G protein subunit alpha 12\/Rho-associated protein kinase-dependent manner to promote myofibroblast differentiation and tissue fibrosis in systemic sclerosis. Arthritis Rheumatol., 1\u201315.","DOI":"10.1002\/art.70228"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1016\/j.molcel.2023.06.012","article-title":"Transcription factors interact with RNA to regulate genes","volume":"83","author":"Oksuz","year":"2023","journal-title":"Mol. Cell"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"gkaf602","DOI":"10.1093\/nar\/gkaf602","article-title":"Synergistic DNA and RNA binding of the Hox transcription factor Ultrabithorax coordinates splicing and shapes in vivo homeotic functions","volume":"53","author":"Blanco","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1101\/gr.225755.117","article-title":"Enhancer RNA profiling predicts transcription factor activity","volume":"28","author":"Azofeifa","year":"2018","journal-title":"Genome Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.canlet.2020.07.040","article-title":"Targeting the radiation-induced TR4 nuclear receptor-mediated QKI\/circZEB1\/miR-141-3p\/ZEB1 signaling increases prostate cancer radiosensitivity","volume":"495","author":"Chen","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1016\/j.cmet.2025.09.003","article-title":"Paternal exercise confers endurance capacity to offspring through sperm microRNAs","volume":"37","author":"Yin","year":"2025","journal-title":"Cell Metab."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Silva-Llanes, I., Shin, C.H., Jim\u00e9nez-Villegas, J., Gorospe, M., and Lastres-Becker, I. (2023). The Transcription Factor NRF2 Has Epigenetic Regulatory Functions Modulating HDACs, DNMTs, and miRNA Biogenesis. Antioxidants, 12.","DOI":"10.3390\/antiox12030641"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1038\/s41388-019-0962-8","article-title":"Targeting the TR4 nuclear receptor-mediated lncTASR\/AXL signaling with tretinoin increases the sunitinib sensitivity to better suppress the RCC progression","volume":"39","author":"Shi","year":"2020","journal-title":"Oncogene"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s00335-025-10172-6","article-title":"Rewiring cancer epigenome: lncRNA as modulator of chromatin architecture and neoplastic transformation","volume":"37","author":"Kumar","year":"2025","journal-title":"Mamm. Genome"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1136\/gutjnl-2021-324305","article-title":"Novel therapeutic targets for cholestatic and fatty liver disease","volume":"71","author":"Trauner","year":"2022","journal-title":"Gut"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1042\/EBC20210020","article-title":"Nuclear receptors: From molecular mechanisms to therapeutics","volume":"65","author":"Frigo","year":"2021","journal-title":"Essays Biochem."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1016\/j.molmed.2021.03.007","article-title":"Drug Discovery Inspired from Nuclear Receptor Sensing of Microbial Signals","volume":"27","author":"Guan","year":"2021","journal-title":"Trends Mol. Med."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"30625","DOI":"10.1021\/acsomega.0c04623","article-title":"Identification of Small-Molecule Regulators of Testicular Receptor 4 via a Drug Repurposing Screening","volume":"5","author":"Xia","year":"2020","journal-title":"ACS Omega"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.bbi.2025.05.027","article-title":"HDAC inhibitors engage MITF and the disease-associated microglia signature to enhance amyloid \u03b2 uptake","volume":"129","author":"Haage","year":"2025","journal-title":"Brain Behav. Immun."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1136\/ard-2021-221269","article-title":"Targeting FoxO transcription factors with HDAC inhibitors for the treatment of osteoarthritis","volume":"82","author":"Ohzono","year":"2023","journal-title":"Ann. Rheum. Dis."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"7919","DOI":"10.1038\/s41467-025-62934-0","article-title":"The HDAC inhibitor romidepsin renders liver cancer vulnerable to RTK targeting and immunologically active","volume":"16","author":"Sequera","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.chembiol.2010.03.006","article-title":"Virtual ligand screening of the p300\/CBP histone acetyltransferase: Identification of a selective small molecule inhibitor","volume":"17","author":"Bowers","year":"2010","journal-title":"Chem. Biol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"21096","DOI":"10.1074\/jbc.272.34.21096","article-title":"Novel inhibitors of cytokine-induced IkappaBalpha phosphorylation and endothelial cell adhesion molecule expression show anti-inflammatory effects in vivo","volume":"272","author":"Pierce","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.1038\/s12276-024-01297-w","article-title":"Telomere stabilization by metformin mitigates the progression of atherosclerosis via the AMPK-dependent p-PGC-1\u03b1 pathway","volume":"56","author":"Sung","year":"2024","journal-title":"Exp. Mol. Med."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/j.cell.2006.11.013","article-title":"Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha","volume":"127","author":"Lagouge","year":"2006","journal-title":"Cell"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"709","DOI":"10.3389\/fphar.2020.00709","article-title":"Changes in PGC-1\u03b1\/SIRT1 Signaling Impact on Mitochondrial Homeostasis in Amyloid-Beta Peptide Toxicity Model","volume":"11","author":"Panes","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"e3148","DOI":"10.1002\/dmrr.3148","article-title":"JAZF1, a relevant metabolic regulator in type 2 diabetes","volume":"35","author":"Liao","year":"2019","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1152\/advan.00052.2006","article-title":"PGC-1alpha: A key regulator of energy metabolism","volume":"30","author":"Liang","year":"2006","journal-title":"Adv. Physiol. Educ."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"025003","DOI":"10.1088\/2632-072X\/ae5864","article-title":"Combination of TRAIL-producing oncolytic virus and PAC-1 for treatment of granulosa cell tumors of the ovary","volume":"7","author":"Nave","year":"2026","journal-title":"J. Phys. Complex."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/13\/1218\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T04:11:46Z","timestamp":1783915906000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/13\/1218"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,3]]},"references-count":117,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["cells15131218"],"URL":"https:\/\/doi.org\/10.3390\/cells15131218","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,3]]}}}