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Pharmacol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Postmenopausal osteoporosis (PMOP) is a prevalent metabolic disorder characterized by pathogenic mechanisms associated with the dysfunction of osteoclasts (OC) and osteoblasts (OB). Icaritin (ICT) is a flavonoid derived from icariin and epimedium, which is a natural product, and has demonstrated promising anti-osteoporosis properties. Nevertheless, the targets and mechanisms of ICT in osteoclast differentiation and PMOP remain unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>we developed a bilateral ovariectomy-induced osteoporosis model in animals and receptor activator of nuclear factor kappa-B ligand (RANKL) induced RAW264.7 to differentiate into osteoclasts with or without MPP dihydrochloride (MPP) and antagomir-503-5p. Micro-CT, tartrate-resistant acid phosphatase (TRAP) staining, enzyme-linked immunosorbent assay (ELISA), Western blot and qRT-PCR were used to detect bone resorption function, bone metabolism parameters, osteoclast differentiation rate and the expression of related genes, as well as the expression of ESR1, miR-503 and RANK. Molecular docking, cell thermal shift assay (CETSA) and drug affinity responsive target stability (DARTs) experiments were used to confirmed that ESR1 is the direct target of ICT, and binding site of ICT with ESR1.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>ICT significantly inhibited OC differentiation and the expression of related genes (<jats:italic>Trap<\/jats:italic>, <jats:italic>Mmp9<\/jats:italic>, and <jats:italic>Nfatc1<\/jats:italic>), reduced bone loss, and improved osteoporosis and bone trabecular structure, and inhibited the levels of TRAP and RANKL in the serum and increase the level of osteoprotegerin (OPG). ICT significantly enhanced the expression of ESR1, ESR2 and miR-503, while inhibiting RANK expression, and ESR1 is the direct target of ICT, and Asparagine at 455 is the direct binding site of ICT with ESR1. Moreover, blocking ESR1 significantly reduced the regulatory effect of ICT on OC differentiation and related gens expression by MPP, especially the expression of miR-503 and RANK, as well as weakened the regulatory effect of ICT on inhibiting bone loss. Antagomir-503-5p significantly reduced the regulatory effect of ICT on OC differentiation, as well as the expression of genes related to OC differentiation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Taken together, our study confirmed that ESR1 is the direct target of ICT, and Asparagine at 455 is the direct binding site of ICT, and ICT inhibits OC differentiation and reduces bone loss by targeting ESR1 to upregulate miR503 level and weaken miR503\/RANK pathway.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1603333","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T09:46:16Z","timestamp":1757670376000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Icaritin inhibits osteoclast differentiation and reduces bone loss by targeting ESR1 to inhibit miR503\/RANK pathway"],"prefix":"10.3389","volume":"16","author":[{"given":"Baoping","family":"Xie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofei","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liuyan","family":"Xin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongliang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinping","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2377","DOI":"10.1007\/s00198-013-2313-x","article-title":"NF-\u03baB signaling and bone resorption","volume":"24","author":"Abu-Amer","year":"2013","journal-title":"Osteoporos. 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