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However, its molecular targets have remained largely unknown. In this study, we characterized the protein targets of \u03b3\u2010CEHC and clarified its role in regulating bone metabolism using an ovariectomized (OVX) mouse model and in\u00a0vitro assays. Bone morphological analysis and histomorphometry demonstrated that \u03b3\u2010CEHC improves osteoporosis in OVX mice by inhibiting osteoclast differentiation and enhancing osteoblast differentiation. To identify the underlying mechanisms, we employed isothermal thermal proteome profiling (TPP) to map \u03b3\u2010CEHC\u2010interacting proteins, followed by Gene Ontology (GO) and KEGG enrichment analyses. Our findings identified fatty acid\u2010binding protein 5 (Fabp5) as a core target. The direct and specific binding between \u03b3\u2010CEHC and Fabp5 was confirmed through cellular thermal shift assays (CETSA), molecular docking\u2014suggesting hydrogen bonding with Thr63\u2014and Surface Plasmon Resonance (SPR) which showed a strong binding affinity (Kd\u2009=\u20095.24\u2009\u03bcM). Furthermore, \u03b3\u2010CEHC was found to suppress LPS\u2010induced M1 macrophage activation and promote M2 polarization, thereby reducing reactive oxygen species (ROS) levels and restoring bone remodeling homeostasis. This study is the first to systematically elucidate the molecular mechanisms of \u03b3\u2010CEHC in bone metabolism, revealing that it acts as a highly selective ligand for Fabp5. These findings provide a novel mechanistic basis for using \u03b3\u2010CEHC and targeting Fabp5 in the treatment of osteoporosis.<\/jats:p>","DOI":"10.1002\/biof.70079","type":"journal-article","created":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T10:47:57Z","timestamp":1768819677000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fabp5 Is the Key Regulator Mediating \u03b3\u2010\n                    <scp>CEHC<\/scp>\n                    Differentiation in Osteoblasts and Osteoclasts"],"prefix":"10.1002","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3406-1963","authenticated-orcid":false,"given":"Cheng","family":"Cheng","sequence":"first","affiliation":[{"name":"Department of Osteoporosis Beijing Jishuitan Hospital, Capital Medical University  Beijing 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China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5903-9151","authenticated-orcid":false,"given":"Xinping","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Osteoporosis Beijing Jishuitan Hospital, Capital Medical University  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gengli","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Osteoporosis Beijing Jishuitan Hospital, Capital Medical University  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7163-6247","authenticated-orcid":false,"given":"Hailing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Osteoporosis Beijing Jishuitan Hospital, Capital Medical University  Beijing 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