{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T00:33:55Z","timestamp":1759365235016,"version":"build-2065373602"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T00:00:00Z","timestamp":1759276800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Legg-Calv\u00e9-Perthes disease (LCPD) is juvenile idiopathic femoral head avascular necrosis with unclear pathophysiology. We aimed to identify circulating metabolic biomarkers and clarify the roles of peripheral inflammation and vascular\/endothelial dysfunction in LCPD, and to evaluate the protective potential of 3-ketoglucose (3-KG) and sanguinarine (SANG).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Peripheral blood from children with LCPD (n=36) and healthy controls (n=6) underwent untargeted LC-MS metabolomics with differential and pathway analyses. Candidate metabolites (3-KG, SANG) were tested in LPS-challenged HUVECs for effects on viability, ROS, IL-1\u03b2\/IL-6\/TNF-\u03b1, and NF-\u03baB\/eNOS\/VCAM-1 (RNA-seq, qPCR, Western blot, immunofluorescence). <jats:italic>In vivo<\/jats:italic> validation used a steroid\/LPS-induced rat model of femoral head osteonecrosis assessing histology, adipogenesis, serum ALP\/TG, and Nos3\/Vcam1\/Nfkb1 expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Thirty-eight metabolites differed significantly between LCPD and controls; 3-KG and SANG were upregulated, whereas several metabolites including N-methyl-D-aspartate were downregulated, mapping to inflammatory and oxidative-stress pathways. Both 3-KG and SANG dose-dependently mitigated LPS-induced HUVEC injury by restoring viability, lowering ROS and pro-inflammatory cytokines, and normalizing NF-\u03baB\/eNOS\/VCAM-1 at mRNA and protein levels, with SANG showing greater potency. In rats, both compounds ameliorated bone loss and adipogenesis, increased ALP, reduced TG, and reversed MPS-induced changes in Nos3, Vcam1 and Nfkb1.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>This work defines a peripheral \u201cmetabolomic fingerprint\u201d of LCPD and links systemic metabolic alterations to endothelial inflammation\/dysfunction. 3-KG and SANG exhibit endothelial-protective activity <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>, supporting their promise as diagnostic biomarkers and therapeutic candidates. Larger, longitudinal cohorts are needed to validate these signatures and clarify stage-specific dynamics.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphys.2025.1641445","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T05:51:44Z","timestamp":1759297904000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolomic profiling reveals novel biomarkers and therapeutic targets in Legg-Calv\u00e9-Perthes disease: a comprehensive analysis of peripheral blood and endothelial function"],"prefix":"10.3389","volume":"16","author":[{"given":"Shaoneng","family":"Zi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengyong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Lv","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiying","family":"Wan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pengju","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong","family":"Hang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongqing","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"9437","DOI":"10.1038\/s41598-025-94018-w","article-title":"Metabolomic profiles in serum uncover novel biomarkers in children with Williams-Beuren syndrome","volume":"15","author":"Bai","year":"2025","journal-title":"Sci. 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