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This study (1) investigates whether calcium and cadmium activation of ESRRB regulates signaling pathways of stemness and pluripotency, (2) explores the transcriptomic and biological alterations of metal activation of ESRRB, and (3) reveals the underlying mechanisms by which metals activate ESRRB. In HEK293T cells, treatment with calcium and cadmium increased the expression of ESRRB-regulated genes that was blocked by an ESRRB antagonist. In the breast cancer cell line MDA-MB-453, treatment with calcium, cadmium, or a synthetic agonist also increased the expression of ESRRB-regulated genes that was blocked by the antagonist, enhanced ESRRB nuclear localization, increased the recruitment of RNA polymerase 2 to estrogen-related receptor response elements (ERRE), enhanced cell stemness and proliferation pathways, and induced the expression of estrogen receptor alpha (ESR1 or Er\u03b1). Mutational analysis and molecular docking identified potential metal interaction sites within ESRRB\u2019s ligand-binding domain. Together, these results suggest calcium acts as a natural ligand for ESRRB and cadmium, which mimics calcium, activate ESRRB to mediate cell stemness and pluripotency.<\/jats:p>","DOI":"10.3390\/ijms27010231","type":"journal-article","created":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T00:50:21Z","timestamp":1766710221000},"page":"231","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Calcium and Cadmium Activate ESRRB to Mediate Cell Stemness and Pluripotency"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-5604-5995","authenticated-orcid":false,"given":"Xu","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC 20007, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9443-1482","authenticated-orcid":false,"given":"Gai","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Oncology, Georgetown University, Washington, DC 20007, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0884-9141","authenticated-orcid":false,"given":"Nicole C.","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC 20007, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0196-0121","authenticated-orcid":false,"given":"Qiaochu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC 20007, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4277-2131","authenticated-orcid":false,"given":"Dajun","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Oncology, Georgetown University, Washington, DC 20007, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0624-5756","authenticated-orcid":false,"given":"Destiny","family":"Lawler","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Howard University, Washington, DC 20059, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reem M.","family":"Gahtani","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC 20007, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8289-4252","authenticated-orcid":false,"given":"Celia","family":"Byrne","sequence":"additional","affiliation":[{"name":"Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2679-3371","authenticated-orcid":false,"given":"Bassem R.","family":"Haddad","sequence":"additional","affiliation":[{"name":"Department of Oncology, Georgetown University, Washington, DC 20007, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9760-6548","authenticated-orcid":false,"given":"Robert L.","family":"Copeland","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Howard University, Washington, DC 20059, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7688-9158","authenticated-orcid":false,"given":"Mary Beth","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC 20007, USA"},{"name":"Department of Oncology, Georgetown University, Washington, DC 20007, USA"},{"name":"Lombardi Comprehensive Cancer Center, Research Building, 3970 Reservoir Road NW, Washington, DC 20007, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1126\/science.1248882","article-title":"Defining an Essential Transcription Factor Program for Na\u00efve 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