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ER\u03b1 is regulated through interactions with various coactivators; however, the precise mechanisms of these interactions are not yet fully understood. We screened for proteins that bind to ER\u03b1 using LC\u2013MS\/MS and identified a physical interaction between HSD17B7 and ER\u03b1, specifically ER\u03b1 binding to the 119\u2013172 domain of HSD17B7. This interaction blocked ubiquitin\u2013proteasomal degradation of ER\u03b1 and increased ERE activity. Estrogen\u2010deficient mice lacking HSD17B7 in their preosteoclasts showed more severe bone loss than control mice. This was attributed to increased mitochondrial biogenesis through the activation of PLD1\u2013mTOR signaling. Additionally, in preosteoclasts derived from patients with severe osteoporosis, the expression of HSD17B7 and ER\u03b1 was significantly reduced compared to the control subjects. Finally, raloxifene, which boosts ER\u03b1, did not inhibit bone loss without HSD17B7, confirming the modulation of ER\u03b1 through HSD17B7. Therefore, HSD17B7 regulation is a novel therapeutic approach for alleviating estrogen\u2010deficient osteoporosis.<\/jats:p>","DOI":"10.1002\/mco2.70623","type":"journal-article","created":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T07:25:41Z","timestamp":1769930741000},"source":"Crossref","is-referenced-by-count":0,"title":["HSD17B7 Counters Bone Loss in Estrogen Deficiency via Estrogen Receptor Stabilization and Mediates the Effect of Raloxifene"],"prefix":"10.1002","volume":"7","author":[{"given":"Junyue","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Jeonbuk National University Medical School  Jeonju Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiping","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Jeonbuk National University Medical School  Jeonju Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeong\u2010Hyun","family":"Koo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Jeonbuk National University Medical School  Jeonju Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Si","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Jeonbuk National University Medical School  Jeonju Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyu Yun","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Pathology Jeonbuk National University Medical School  Jeonju Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sun\u2010Jung","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Jeonbuk National University Medical School  Jeonju Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jung Ryul","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Jeonbuk National University Medical School  Jeonju Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Young Jae","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Jeonbuk National University Medical School  Jeonju Republic of Korea"},{"name":"Department of Orthopaedic Surgery Jeonbuk National University Hospital Jeonju Republic of Korea"},{"name":"Research Institute of Clinical Medicine, Medical Sciences, and Biomedical Research Institute Jeonbuk National University and Hospital Jeonju Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,1,31]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00198-021-05900-y"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)02800-3"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.3400"},{"issue":"11","key":"e_1_2_11_5_1","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1038\/nm.4385","article-title":"Targeting Cellular Senescence Prevents Age\u2010Related Bone Loss in Mice","volume":"23","author":"Farr J. 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