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In this study, we explored the therapeutic effects and underlying mechanisms of 6-HOF in LPS-induced osteoclastogenesis and inflammatory bone loss. Network pharmacology analysis predicted that 6-HOF primarily targets oxidative stress and calcium signaling pathways. In vitro, 6-HOF inhibited multinucleated osteoclast formation in a concentration-dependent manner without affecting cell viability, downregulated osteoclast-specific genes including\n                    <jats:italic>Nfatc1<\/jats:italic>\n                    ,\n                    <jats:italic>Ctsk<\/jats:italic>\n                    ,\n                    <jats:italic>Dc-stamp<\/jats:italic>\n                    , and\n                    <jats:italic>Mmp9<\/jats:italic>\n                    , and significantly reduced the expression and secretion of pro-inflammatory cytokines IL-6, TNF-\u03b1, and IL-1\u03b2. Mechanistically, 6-HOF suppressed intracellular ROS accumulation, disrupted RANKL-induced Ca\u00b2\u207a oscillations, and inhibited NFATc1 signaling essential for osteoclast differentiation, while activating the Keap1\/Nrf2 antioxidant pathway to restore redox homeostasis. In vivo, micro-CT analyses showed that 6-HOF treatment alleviated LPS-induced bone loss by reducing osteoclast numbers and preserving trabecular microarchitecture. Collectively, these results indicate that 6-HOF inhibits osteoclastogenesis and inflammatory responses through the dual regulation of oxidative stress, calcium signaling, and pro-inflammatory cytokine production, highlighting its potential as a promising therapeutic candidate for IO and other bone-destructive disorders.\n                  <\/jats:p>","DOI":"10.1007\/s10753-026-02500-y","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T21:05:59Z","timestamp":1775855159000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["6-Hydroxyflavone Attenuates Inflammatory Osteolysis by Inhibiting Osteoclast Activation via the Nrf2 and Calcium Signaling Pathways"],"prefix":"10.1007","volume":"49","author":[{"given":"Kun","family":"Qian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qizhen","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiyi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qige","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenghong","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanyun","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shui","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"2500_CR1","doi-asserted-by":"publisher","first-page":"2030","DOI":"10.1172\/JCI93356","volume":"127","author":"G Mbalaviele","year":"2017","unstructured":"Mbalaviele, G., D. 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