{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T06:15:10Z","timestamp":1788243310839,"version":"build-2803163510"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"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. Mol. Biosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Osteosarcoma remains the most prevalent primary malignant bone tumor in adolescents and young adults. For patients with localized disease, 5-year overall survival reaches 60%\u201370%; however, for those with metastatic or recurrent disease, 5-year survival remains stagnant at approximately 20%, and chemoresistance represents the primary obstacle to improved outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This review systematically elucidates the crosstalk among glycolytic, lipid, and glutamine pathways and their synergistic interactions with the immune microenvironment in driving osteosarcoma drug resistance, while evaluating the translational potential of metabolic targeted therapies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We highlight that aerobic glycolysis-derived histone lactylation, which has been shown to activate multidrug resistance gene transcription in other cancers and represents a candidate epigenetic mechanism warranting investigation in osteosarcoma; SCD1-mediated monounsaturated fatty acid synthesis confers ferroptosis resistance; glutamine-derived \u03b1-KG supports epigenetic programming and redox homeostasis; and metabolic competition creates an immunosuppressive tumor microenvironment. We further discuss metabolic heterogeneity, plasticity, and metabolomic methodologies as applied to osteosarcoma.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Single-agent metabolic inhibitors show limited clinical efficacy due to metabolic plasticity and compensatory activation. Almost all metabolic targeting evidence remains preclinical; no metabolic therapy has yet entered standard osteosarcoma care. Triple combination strategies (metabolic inhibitors + immunotherapy + chemotherapy) represent a mechanistically attractive but clinically untested hypothesis. Telaglenastat (CB-839), a glutaminase inhibitor, has been prioritized for osteosarcoma clinical trials but efficacy data in osteosarcoma patients remain pending.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmolb.2026.1928880","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T05:35:54Z","timestamp":1788240954000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic reprogramming-related drug resistance in osteosarcoma: from molecular mechanisms to therapeutic translation"],"prefix":"10.3389","volume":"13","author":[{"given":"Qun","family":"Wu","sequence":"first","affiliation":[{"name":"First Ward of Orthopedics, Loudi Central Hospital","place":["Loudi, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxiang","family":"Chen","sequence":"additional","affiliation":[{"name":"First Ward of Orthopedics, Loudi Central Hospital","place":["Loudi, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Li","sequence":"additional","affiliation":[{"name":"First Ward of Orthopedics, Loudi Central Hospital","place":["Loudi, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3946","DOI":"10.3390\/ijms24043946","article-title":"The illustration of altered glucose dependency in drug-resistant cancer cells","volume":"24","author":"Bishayee","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"vii100","DOI":"10.1093\/annonc\/mds254","article-title":"ESMO\/european sarcoma network working group. Bone sarcomas: ESMO clinical practice guidelines for diagnosis, treatment and follow-up","volume":"23","author":"Casali","year":"2012","journal-title":"Ann. Oncol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"950886","DOI":"10.3389\/fphar.2022.950886","article-title":"The roles of glycolysis in osteosarcoma","volume":"13","author":"Feng","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"2189","DOI":"10.3390\/cancers13092189","article-title":"Progression-dependent altered metabolism in osteosarcoma resulting in different nutrient source dependencies","volume":"13","author":"Fritsche-Guenther","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B5","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1038\/s41574-020-0363-1","article-title":"Germline and somatic genetics of osteosarcoma - connecting aetiology, biology and therapy","volume":"16","author":"Gianferante","year":"2020","journal-title":"Nat. Rev. Endocrinol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"2786","DOI":"10.3390\/cancers14112786","article-title":"Advancing cancer treatment by targeting glutamine Metabolism-A roadmap","volume":"14","author":"Halama","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B7","doi-asserted-by":"publisher","first-page":"5621","DOI":"10.3390\/ijms24065621","article-title":"Strategies to overcome resistance to immune-based therapies in osteosarcoma","volume":"24","author":"Hattinger","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1001318","DOI":"10.3389\/fonc.2022.1001318","article-title":"Amino acid metabolism in primary bone sarcomas","volume":"12","author":"Jimenez","year":"2022","journal-title":"Front. Oncol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1038\/s12276-023-00971-9","article-title":"Targeting glutamine metabolism as a therapeutic strategy for cancer","volume":"55","author":"Jin","year":"2023","journal-title":"Exp. Mol. Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"948097","DOI":"10.3389\/fcell.2022.948097","article-title":"Insight into the interplay between mitochondria-regulated cell death and energetic metabolism in osteosarcoma","volume":"10","author":"Lai","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1002\/jcp.30560","article-title":"Multiple functions of pyruvate kinase M2 in various cell types","volume":"237","author":"Lee","year":"2022","journal-title":"J. Cell Physiol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"8830","DOI":"10.1038\/s41598-024-63736-y","article-title":"Machine learning survival prediction using tumor lipid metabolism genes for osteosarcoma","volume":"14","author":"Li","year":"2024","journal-title":"Sci. Rep."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1342567","DOI":"10.3389\/fcell.2024.1342567","article-title":"Advancements in osteosarcoma management: integrating immune microenvironment insights with immunotherapeutic strategies","volume":"12","author":"Liang","year":"2024","journal-title":"Front. Cell Dev. Biol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"6885","DOI":"10.3390\/ijms21186885","article-title":"Targeting molecular mechanisms underlying treatment efficacy and resistance in osteosarcoma: a review of current and future strategies","volume":"21","author":"Lilienthal","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1031779","DOI":"10.3389\/fonc.2022.1031779","article-title":"Ferroptosis in osteosarcoma: a promising future","volume":"12","author":"Liu","year":"2022","journal-title":"Front. Oncol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"830546","DOI":"10.3389\/fonc.2022.830546","article-title":"Novel immunotherapies for osteosarcoma","volume":"12","author":"Lu","year":"2022","journal-title":"Front. Oncol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1038\/s41419-023-06273-2","article-title":"The BRD4-SRPK2-SRSF2 signal modulates the splicing efficiency of ACSL3 pre-mRNA and influences erastin-induced ferroptosis in osteosarcoma cells","volume":"14","author":"Luo","year":"2023","journal-title":"Cell Death Dis."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1531","DOI":"10.1002\/cncr.24121","article-title":"Osteosarcoma incidence and survival rates from 1973 to 2004: data from the surveillance, epidemiology, and end results program","volume":"115","author":"Mirabello","year":"2009","journal-title":"Cancer"},{"key":"B50","doi-asserted-by":"publisher","first-page":"1610231","DOI":"10.3389\/pore.2022.1610231","article-title":"In situ analysis of mTORC1\/C2 and metabolism-related proteins in pediatric osteosarcoma","volume":"28","author":"Moh\u00e1s","year":"2024","journal-title":"Pathol. Oncol. Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1953","DOI":"10.1038\/s41401-024-01097-8","article-title":"Transcriptional regulation and post-translational modifications in the glycolytic pathway for targeted cancer therapy","volume":"45","author":"Ni","year":"2024","journal-title":"Acta Pharmacol. Sin."},{"key":"B21","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/978-1-4419-0284-9_1","article-title":"The epidemiology of osteosarcoma","volume":"152","author":"Ottaviani","year":"2009","journal-title":"Cancer Treat. Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"3706","DOI":"10.3390\/ijms24043706","article-title":"Promise and challenges of T cell immunotherapy for osteosarcoma","volume":"24","author":"Park","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.cmet.2015.12.006","article-title":"The emerging hallmarks of cancer metabolism","volume":"23","author":"Pavlova","year":"2016","journal-title":"Cell Metab."},{"key":"B24","doi-asserted-by":"publisher","first-page":"597","DOI":"10.3894\/ol.2021.12630","article-title":"Altered glycolysis results in drug-resistant in clinical tumor therapy","volume":"22","author":"Peng","year":"2021","journal-title":"Oncol. Lett."},{"key":"B25","doi-asserted-by":"publisher","first-page":"746030","DOI":"10.3389\/fonc.2022.746030","article-title":"Novel therapeutic savior for osteosarcoma: the endorsement of ferroptosis","volume":"12","author":"Qiu","year":"2022","journal-title":"Front. Oncol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"108578","DOI":"10.1016\/j.celrep.2020.108578","article-title":"Metabolic compensation activates pro-survival mTORC1 signaling upon 3-phosphoglycerate dehydrogenase inhibition in osteosarcoma","volume":"34","author":"Rathore","year":"2021","journal-title":"Cell Rep."},{"key":"B27","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21708","article-title":"Cancer statistics, 2022","volume":"72","author":"Siegel","year":"2022","journal-title":"CA Cancer J. Clin."},{"key":"B39","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1038\/s41556-024-01464-1","article-title":"Zeb1 mediates EMT\/plasticity-associated ferroptosis sensitivity in cancer cells by regulating lipogenic enzyme expression and phospholipid composition","volume":"26","author":"Schwab","year":"2024","journal-title":"Nat. Cell Biol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1352867","DOI":"10.3389\/fimmu.2024.1352867","article-title":"Osteosarcoma immunometabolism: emerging mechanisms and clinical implications","volume":"15","author":"Tan","year":"2024","journal-title":"Front. Immunol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00280-021-04278-5","article-title":"The role of the glutamine transporter ASCT2 in antineoplastic therapy","volume":"88","author":"Teixeira","year":"2021","journal-title":"Cancer Chemother. Pharmacol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"103627","DOI":"10.1016\/j.ebiom.2021.103627","article-title":"Lactate in the tumour microenvironment: from immune modulation to therapy","volume":"73","author":"Wang","year":"2021","journal-title":"EBioMedicine"},{"key":"B31","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1186\/s13046-024-02994-0","article-title":"A glutamine tug-of-war between cancer and immune cells: recent advances in unraveling the ongoing battle","volume":"43","author":"Wang","year":"2024","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"4717","DOI":"10.1158\/1078-0432.CCR-21-0668","article-title":"Charting a path for prioritization of novel agents for clinical trials in osteosarcoma: a report from the children's oncology group new agents for osteosarcoma task force","volume":"27","author":"Whittle","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"997","DOI":"10.4155\/fmc-2020-0360","article-title":"Structural and functional regulation of lactate dehydrogenase-A in cancer","volume":"13","author":"Woodford","year":"2021","journal-title":"Future Med. Chem."},{"key":"B34","doi-asserted-by":"publisher","first-page":"934080","DOI":"10.3389\/fonc.2022.934080","article-title":"Comprehensive analysis of fatty acid and lactate metabolism-related genes for prognosis value, immune infiltration, and therapy in osteosarcoma patients","volume":"12","author":"Wu","year":"2022","journal-title":"Front. Oncol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"135","DOI":"10.21147\/j.issn.1000-9604.2019.01.08","article-title":"Incidence and mortality of primary bone cancers in China, 2014","volume":"31","author":"Xia","year":"2019","journal-title":"Chin. J. Cancer Res."},{"key":"B36","doi-asserted-by":"publisher","first-page":"e37915","DOI":"10.1016\/j.heliyon.2024.e37915","article-title":"Lactate and lysine lactylation of histone regulate transcription in cancer","volume":"10","author":"Yang","year":"2024","journal-title":"Heliyon"},{"key":"B37","doi-asserted-by":"publisher","first-page":"100458","DOI":"10.1016\/j.jbo.2024.100458","article-title":"Lipid metabolic reprogramming and associated ferroptosis in osteosarcoma: from molecular mechanisms to potential targets","volume":"45","author":"Yin","year":"2024","journal-title":"J. Bone Oncol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"871076","DOI":"10.3389\/fimmu.2022.871076","article-title":"Effects of microenvironment in osteosarcoma on chemoresistance and the promise of immunotherapy as an osteosarcoma therapeutic modality","volume":"13","author":"Yu","year":"2022","journal-title":"Front. Immunol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1091779","DOI":"10.3389\/fphar.2022.1091779","article-title":"The significance of glycolysis in tumor progression and its relationship with the tumor microenvironment","volume":"13","author":"Zhou","year":"2023","journal-title":"Front. Pharmacol."}],"container-title":["Frontiers in Molecular Biosciences"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2026.1928880\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T05:35:55Z","timestamp":1788240955000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2026.1928880\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,1]]},"references-count":40,"alternative-id":["10.3389\/fmolb.2026.1928880"],"URL":"https:\/\/doi.org\/10.3389\/fmolb.2026.1928880","relation":{},"ISSN":["2296-889X"],"issn-type":[{"value":"2296-889X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,1]]},"article-number":"1928880"}}