{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T05:06:22Z","timestamp":1779080782484,"version":"3.51.4"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"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. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Osteoporosis is a systemic skeletal disease characterized by excessive osteoclast-mediated bone resorption. This study aimed to evaluate the therapeutic potential of 5-methoxyresorcinol (MR) in osteoporosis and to clarify its underlying mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Network pharmacology analysis was performed to identify shared targets between MR and osteoporosis.\n                      <jats:italic>In vitro<\/jats:italic>\n                      experiments using bone marrow-derived macrophages were performed to assess the effects of MR on osteoclast differentiation and function. In addition, the\n                      <jats:italic>in vivo<\/jats:italic>\n                      efficacy of MR was evaluated in an ovariectomized (OVX) mouse model using micro-CT and histological analyses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Network pharmacology analysis identified 107 potential targets of MR and 8,060 osteoporosis-associated genes, of which 50 were overlapping targets. Among these targets, the PI3K\u2013AKT signaling pathway showed significant enrichment.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , MR at concentrations \u22641\u00a0mM showed no significant cytotoxicity and suppressed osteoclast differentiation in a dose-dependent manner. MR also inhibited osteoclast function by reducing the formation of F-actin ring and the secretion of acidified vesicles. Mechanistically, MR inhibited activation of the PI3K\u2013AKT\u2013GSK3\u03b2 pathway, downregulated osteoclast-specific genes (DC-STAMP, OC-STAMP, CTSK, MMP-9, c-FOS, and NFATc1), and reduced RANKL-induced reactive oxygen species (ROS) generation. In OVX mice, MR improved bone microarchitecture and alleviated osteoporotic bone loss.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>MR attenuates osteoporosis by suppressing osteoclast differentiation and function through regulating PI3K\u2013AKT\u2013GSK3\u03b2 axis and ROS homeostasis, supporting its potential as a promisingtherapeutic candidate for osteoporosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1734275","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T04:18:00Z","timestamp":1779077880000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["5-methoxyresorcinol mitigates postmenopausal osteoporosis through regulation of the PI3K\u2013AKT\u2013GSK3\u03b2 signaling pathway and ROS homeostasis"],"prefix":"10.3389","volume":"17","author":[{"given":"Maosheng","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Joint Surgery and Sports Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rongrong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery and Sports Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanbin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery and Sports Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yitong","family":"Geng","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery and Sports Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiyuan","family":"Yv","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery and Sports Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinqiao","family":"Qiao","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery and Sports Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery and Sports Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"102726","DOI":"10.1016\/j.redox.2023.102726","article-title":"The KEAP1-NRF2 pathway: targets for therapy and role in cancer","volume":"63","author":"Adinolfi","year":"2023","journal-title":"Redox Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"477","DOI":"10.2217\/whe.15.14","article-title":"Prediction of fracture risk in patients with osteoporosis: a brief review","volume":"11","author":"Arceo-Mendoza","year":"2015","journal-title":"Womens Health (Lond)"},{"key":"B3","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1016\/j.freeradbiomed.2025.11.054","article-title":"Gut microbial metabolite alleviates osteoporosis by attenuating AKT-NFATc1 signaling pathway and ROS production","volume":"243","author":"Bai","year":"2026","journal-title":"Free Radic. Biol. Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1038\/nature01658","article-title":"Osteoclast differentiation and activation","volume":"423","author":"Boyle","year":"2003","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e0296756","DOI":"10.1371\/journal.pone.0296756","article-title":"Assessment of antimalarial activity of crude extract of Chan-Ta-Lee-La and Pra-Sa-Chan-Dang formulations and their plant ingredients for new drug candidates of malaria treatment: in vitro and in vivo experiments","volume":"19","author":"Chaniad","year":"2024","journal-title":"PLoS One"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.3389\/fphar.2018.01046","article-title":"Boldine ameliorates estrogen deficiency-induced bone loss via inhibiting bone resorption","volume":"9","author":"Chen","year":"2018","journal-title":"Front. Pharmacol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"9067","DOI":"10.1111\/jcmm.15543","article-title":"Neobavaisoflavone inhibits osteoclastogenesis through blocking RANKL signalling-mediated TRAF6 and c-Src recruitment and NF-\u03baB, MAPK and Akt pathways","volume":"24","author":"Chen","year":"2020","journal-title":"J. Cell Mol. Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1038\/s41419-022-04963-x","article-title":"The role of the PI3K\/AKT signalling pathway in the corneal epithelium: recent updates","volume":"13","author":"Chen","year":"2022","journal-title":"Cell Death Dis."},{"key":"B9","doi-asserted-by":"publisher","first-page":"101842","DOI":"10.1016\/j.arr.2023.101842","article-title":"Physiological functions of podosomes: from structure and function to therapy implications in osteoclast biology of bone resorption","volume":"85","author":"Chen","year":"2023","journal-title":"Ageing Res. Rev."},{"key":"B10","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1016\/j.freeradbiomed.2024.12.036","article-title":"Baicalein disrupts the KEAP1-NRF2 interaction to alleviate oxidative stress injury by inhibiting M1 macrophage polarization","volume":"227","author":"Chi","year":"2025","journal-title":"Free Radic. Biol. Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1038\/378785a0","article-title":"Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B","volume":"378","author":"Cross","year":"1995","journal-title":"Nature"},{"key":"B12","doi-asserted-by":"publisher","first-page":"4913534","DOI":"10.1155\/2022\/4913534","article-title":"Network pharmacology deciphers the action of bioactive polypeptide in attenuating inflammatory osteolysis via the suppression of oxidative stress and restoration of bone remodeling balance","volume":"2022","author":"Cui","year":"2022","journal-title":"Oxid. Med. Cell Longev."},{"key":"B13","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1002\/jbmr.3337","article-title":"Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension","volume":"33","author":"Cummings","year":"2018","journal-title":"J. Bone Min. Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e70044","DOI":"10.1111\/jcmm.70044","article-title":"Crebanine mitigates glucocorticoid-induced osteonecrosis of the femoral head by restoring bone remodelling homeostasis via attenuating oxidative stress","volume":"28","author":"Dong","year":"2024","journal-title":"J. Cell Mol. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"116538","DOI":"10.1016\/j.bone.2022.116538","article-title":"The origins and formation of bone-resorbing osteoclasts","volume":"164","author":"Elson","year":"2022","journal-title":"Bone"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e580","DOI":"10.1016\/S2666-7568(21)00172-0","article-title":"Global, regional, and national burden of bone fractures in 204 countries and territories, 1990\u20132019: a systematic analysis from the global burden of disease study 2019","volume":"2","year":"2021","journal-title":"Lancet Healthy Longev."},{"key":"B17","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1007\/s00198-019-05229-7","article-title":"Impact of whole dairy matrix on musculoskeletal health and aging-current knowledge and research gaps","volume":"31","author":"Geiker","year":"2020","journal-title":"Osteoporos. Int."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3390\/antiox9111136","article-title":"Osteoprotective roles of green tea catechins","volume":"9","author":"Huang","year":"2020","journal-title":"Antioxidants (Basel)"},{"key":"B19","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1210\/me.2007-0237","article-title":"NFATc1 induces osteoclast fusion via up-regulation of Atp6v0d2 and the dendritic cell-specific transmembrane protein (DC-STAMP)","volume":"22","author":"Kim","year":"2008","journal-title":"Mol. Endocrinol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"4717","DOI":"10.3390\/ijms22094717","article-title":"Lumican inhibits osteoclastogenesis and bone resorption by suppressing akt activity","volume":"22","author":"Lee","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1002\/jbmr.242","article-title":"Maslinic acid suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss by regulating RANKL-mediated NF-\u03baB and MAPK signaling pathways","volume":"26","author":"Li","year":"2011","journal-title":"J. Bone Min. Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1489","DOI":"10.2174\/0929867327666200330142432","article-title":"Osteoporosis: mechanism, molecular target and current status on drug development","volume":"28","author":"Li","year":"2021","journal-title":"Curr. Med. Chem."},{"key":"B23","doi-asserted-by":"publisher","first-page":"116166","DOI":"10.1016\/j.biopha.2024.116166","article-title":"Corylifol A suppresses osteoclastogenesis and alleviates ovariectomy-induced bone loss via attenuating ROS production and impairing mitochondrial function","volume":"171","author":"Li","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"B24","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1186\/s10020-024-00893-w","article-title":"Epimedin A inhibits the PI3K\/AKT\/NF-\u03baB signalling axis and osteoclast differentiation by negatively regulating TRAF6 expression","volume":"30","author":"Li","year":"2024","journal-title":"Mol. Med."},{"key":"B25","doi-asserted-by":"publisher","first-page":"116933","DOI":"10.1016\/j.biopha.2024.116933","article-title":"Hecogenin alleviates LPS-induced osteolysis via regulating pyroptosis and ROS involved Nrf2 activation","volume":"177","author":"Liu","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"B26","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1186\/s11658-024-00614-5","article-title":"New mechanistic understanding of osteoclast differentiation and bone resorption mediated by P2X7 receptors and PI3K-Akt-GSK3\u03b2 signaling","volume":"29","author":"Lu","year":"2024","journal-title":"Cell Mol. Biol. Lett."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1435","DOI":"10.1210\/clinem\/dgz321","article-title":"Delayed denosumab injections and bone mineral density response: an electronic health record-based study","volume":"105","author":"Lyu","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B28","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1210\/edrv.21.2.0395","article-title":"Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis","volume":"21","author":"Manolagas","year":"2000","journal-title":"Endocr. Rev."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1696","DOI":"10.1083\/jcb.99.5.1696","article-title":"Cell-substratum interaction of cultured Avian osteoclasts is mediated by specific adhesion structures","volume":"99","author":"Marchisio","year":"1984","journal-title":"J. Cell Biol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1172\/JCI90527","article-title":"RANKL coordinates multiple osteoclastogenic pathways by regulating expression of ubiquitin ligase RNF146","volume":"127","author":"Matsumoto","year":"2017","journal-title":"J. Clin. Invest."},{"key":"B31","doi-asserted-by":"publisher","first-page":"26475","DOI":"10.1074\/jbc.M313973200","article-title":"Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos","volume":"279","author":"Matsuo","year":"2004","journal-title":"J. Biol. Chem."},{"key":"B32","doi-asserted-by":"publisher","first-page":"104976","DOI":"10.1016\/j.bioorg.2021.104976","article-title":"Briarane-type diterpenoids suppress osteoclastogenisis by regulation of Nrf2 and MAPK\/NF-kB signaling pathway","volume":"112","author":"Meng","year":"2021","journal-title":"Bioorg Chem."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.2174\/0109298673371731250415115235","article-title":"Spinosin suppresses RANKL-induced osteoclastogenesis and alleviates LPS-induced cranial osteolysis: a study based on network pharmacology and experimental validation","author":"Meng","year":"2025","journal-title":"Curr. Med. Chem."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1002\/jbmr.1575","article-title":"Osteoclast stimulatory transmembrane protein and dendritic cell\u2013specific transmembrane protein cooperatively modulate cell\u2013cell fusion to form osteoclasts and foreign body giant cells","volume":"27","author":"Miyamoto","year":"2012","journal-title":"J. Bone Min. Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1185\/03007995.2015.1016605","article-title":"Cost and consequences of noncompliance with osteoporosis treatment among women initiating therapy","volume":"31","author":"Modi","year":"2015","journal-title":"Curr. Med. Res. Opin."},{"key":"B36","doi-asserted-by":"publisher","first-page":"163","DOI":"10.4049\/jimmunol.1101254","article-title":"Akt induces osteoclast differentiation through regulating the GSK3\u03b2\/NFATc1 signaling cascade","volume":"188","author":"Moon","year":"2012","journal-title":"J. Immunol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1001\/jama.2025.6003","article-title":"Osteoporosis: a review","author":"Morin","year":"2025","journal-title":"Jama"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1152\/physrev.00036.2016","article-title":"Osteoimmunology: the conceptual framework unifying the immune and skeletal systems","volume":"97","author":"Okamoto","year":"2017","journal-title":"Physiol. Rev."},{"key":"B39","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1002\/cyto.a.22495","article-title":"Evaluation of acridine orange, LysoTracker Red, and quinacrine as fluorescent probes for long-term tracking of acidic vesicles","volume":"85","author":"Pierzy\u0144ska-Mach","year":"2014","journal-title":"Cytom. A"},{"key":"B40","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1186\/s12906-022-03678-y","article-title":"Exploring in vitro anti-proliferative and anti-inflammatory activities of Prasachandaeng remedy, and its bioactive compounds","volume":"22","author":"Prommee","year":"2022","journal-title":"BMC Complement. Med. Ther."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1276","DOI":"10.1016\/S0140-6736(10)62349-5","article-title":"Osteoporosis: now and the future","volume":"377","author":"Rachner","year":"2011","journal-title":"Lancet"},{"key":"B42","doi-asserted-by":"publisher","first-page":"485","DOI":"10.4314\/ajtcam.v9i4.5","article-title":"Anti-inflammatory and anti-ulcerogenic activities of Chantaleela recipe","volume":"9","author":"Sireeratawong","year":"2012","journal-title":"Afr. J. Tradit. Complement. Altern. Med."},{"key":"B43","doi-asserted-by":"publisher","first-page":"2500","DOI":"10.3390\/ijms23052500","article-title":"Fibroblast growth factor 23 and osteoporosis: evidence from bench to bedside","volume":"23","author":"Sirikul","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B44","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1016\/s1534-5807(02)00369-6","article-title":"Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts","volume":"3","author":"Takayanagi","year":"2002","journal-title":"Dev. Cell"},{"key":"B45","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1007\/s10753-023-01933-z","article-title":"Inhibition of protein disulfide isomerase attenuates osteoclast differentiation and function via the readjustment of cellular redox state in postmenopausal osteoporosis","volume":"47","author":"Wang","year":"2024","journal-title":"Inflammation"},{"key":"B46","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1186\/s13075-025-03522-x","article-title":"Quercetagetin alleviates inflammatory osteoclastogenesis and collagen antibody-induced arthritis via Nrf2 signaling and Pten\/AKT\/Nfatc1 axis","volume":"27","author":"Wang","year":"2025","journal-title":"Arthritis Res. Ther."},{"key":"B47","doi-asserted-by":"publisher","first-page":"2817","DOI":"10.1080\/15548627.2022.2048432","article-title":"TET2 regulates osteoclastogenesis by modulating autophagy in OVX-induced bone loss","volume":"18","author":"Yang","year":"2022","journal-title":"Autophagy"},{"key":"B48","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1186\/s12967-023-04706-2","article-title":"Myrislignan targets extracellular signal-regulated kinase (ERK) and modulates mitochondrial function to dampen osteoclastogenesis and ovariectomy-induced osteoporosis","volume":"21","author":"Yang","year":"2023","journal-title":"J. Transl. Med."},{"key":"B49","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1002\/med.22081","article-title":"Estrogen deficiency-mediated osteoimmunity in postmenopausal osteoporosis","volume":"45","author":"Yao","year":"2025","journal-title":"Med. Res. Rev."},{"key":"B50","doi-asserted-by":"publisher","first-page":"e35374","DOI":"10.1016\/j.heliyon.2024.e35374","article-title":"Suppressing ERp57 diminishes osteoclast activity and ameliorates ovariectomy-induced bone loss via the intervention in calcium oscillation and the calmodulin\/calcineurin\/Nfatc1 pathway","volume":"10","author":"Yuan","year":"2024","journal-title":"Heliyon"},{"key":"B51","doi-asserted-by":"publisher","first-page":"123","DOI":"10.3389\/fphar.2019.00123","article-title":"Network pharmacology databases for traditional Chinese medicine: review and assessment","volume":"10","author":"Zhang","year":"2019","journal-title":"Front. Pharmacol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"6638","DOI":"10.7150\/thno.44793","article-title":"Genetic and pharmacological activation of Hedgehog signaling inhibits osteoclastogenesis and attenuates titanium particle-induced osteolysis partly through suppressing the JNK\/c-Fos-NFATc1 cascade","volume":"10","author":"Zhang","year":"2020","journal-title":"Theranostics"},{"key":"B53","doi-asserted-by":"publisher","first-page":"153377","DOI":"10.1016\/j.phymed.2020.153377","article-title":"Kirenol inhibits RANKL-induced osteoclastogenesis and prevents ovariectomized-induced osteoporosis via suppressing the Ca(2+)-NFATc1 and Cav-1 signaling pathways","volume":"80","author":"Zou","year":"2021","journal-title":"Phytomedicine"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1734275\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T04:18:01Z","timestamp":1779077881000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1734275\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,18]]},"references-count":53,"alternative-id":["10.3389\/fphar.2026.1734275"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1734275","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,18]]},"article-number":"1734275"}}