{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T03:01:17Z","timestamp":1791860477781,"version":"4.3.4"},"reference-count":33,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Central chondrosarcoma is the second most common primary malignant bone tumour, and grade progression markedly worsens prognosis. The contributions of lipid metabolic reprogramming and epigenetic co-dysregulation to grade progression remain poorly characterised. We integrated a bulk RNA-seq discovery cohort of 53 graded central chondrosarcomas (GSE299759) with a single-cell analysis of eight chondrosarcomas (GSE184118). Because the atypical cartilaginous tumour (ACT) and dedifferentiated groups each comprised only three samples, the Grade 3 versus Grade 2 contrast was pre-specified as the primary comparison. Curated panels of 44 lipid metabolism genes and 50 epigenetic regulators were assessed by differential expression and a correlation-based connectivity ranking, evaluated by permutation testing. In the primary Grade 3 versus Grade 2 comparison, SQLE, ACACA, and FASN were upregulated (FDR &lt; 0.05), indicating a grade-associated increase in de novo lipogenesis. In the exploratory Grade 3 versus ACT comparison, additional lipid genes (HMGCR, LDLRAP1) and the epigenetic regulators EHMT2 and SIRT2 showed altered expression, although the small ACT group limits these estimates. A connectivity ranking highlighted FASN, KMT2C, TET2, SETD5, and KDM5B; permutation testing confirmed this co-expression structure was non-random (p &lt; 0.0001). Single-cell analysis showed FASN, SETD5, and KDM5B are expressed predominantly in malignant cells, whereas KMT2C and TET2 are not, indicating cell-type heterogeneity. De novo lipogenesis upregulation is the most consistent lipid alteration in high-grade central chondrosarcoma, nominating SQLE, ACACA, and FASN as candidates for experimental investigation.<\/jats:p>","DOI":"10.3390\/ijms27125307","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T06:53:10Z","timestamp":1781247190000},"page":"5307","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Lipid Metabolic Reprogramming and Epigenetic Co-Dysregulation Across the Central Chondrosarcoma Grade Spectrum: A Multi-Cohort RNA-seq Study"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5848-1618","authenticated-orcid":false,"given":"Batuhan","family":"Ayhan","sequence":"first","affiliation":[{"name":"Department of Orthopaedics and Traumatology, Haymana State Hospital, Haymana, 06860 Ankara, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5178-3004","authenticated-orcid":false,"given":"Neslihan","family":"D\u00f6nmez","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Graduate School of Health Sciences, Hacettepe University, 06100 Ankara, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeliha Deniz","family":"Ayhan","sequence":"additional","affiliation":[{"name":"Department of Medical Pathology, Faculty of Medicine, Gazi University, 06560 Ankara, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/978-3-319-07323-1_6","article-title":"Chondrosarcoma of bone","volume":"162","author":"Leddy","year":"2014","journal-title":"Cancer Treat. Res."},{"key":"ref_2","unstructured":"WHO Classification of Tumours Editorial Board (2020). Soft Tissue and Bone Tumours, IARC Press. [5th ed.]."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/S1470-2045(05)70282-5","article-title":"Emerging pathways in the development of chondrosarcoma of bone","volume":"6","author":"Taminiau","year":"2005","journal-title":"Lancet Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.1111\/cas.15382","article-title":"Clinical features and treatment outcomes of dedifferentiated and grade 3 chondrosarcoma: A multi-institutional study","volume":"113","author":"Kozawa","year":"2022","journal-title":"Cancer Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1002\/path.2913","article-title":"IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours","volume":"224","author":"Amary","year":"2011","journal-title":"J. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1158\/1078-0432.CCR-18-4212","article-title":"Genomic profiling identifies association of IDH1\/IDH2 mutation with longer relapse-free and metastasis-free survival in high-grade chondrosarcoma","volume":"26","author":"Zhu","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"100894","DOI":"10.1016\/j.modpat.2025.100894","article-title":"An integrated clinical genomic and transcriptomic subgrouping of central chondrosarcoma","volume":"38","author":"Meijer","year":"2025","journal-title":"Mod. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1038\/nature08617","article-title":"Cancer-associated IDH1 mutations produce 2-hydroxyglutarate","volume":"462","author":"Dang","year":"2009","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of cancer: New dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1186\/s13045-023-01498-2","article-title":"Lipid metabolic reprogramming in tumor microenvironment: From mechanisms to therapeutics","volume":"16","author":"Jin","year":"2023","journal-title":"J. Hematol. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1038\/nrc2222","article-title":"Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis","volume":"7","author":"Menendez","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.cmet.2013.05.017","article-title":"Cellular fatty acid metabolism and cancer","volume":"18","author":"Currie","year":"2013","journal-title":"Cell Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"100660","DOI":"10.1016\/j.jbo.2025.100660","article-title":"Lipid metabolic reprogramming and associated ferroptosis in osteosarcoma: From molecular mechanisms to potential targets","volume":"51","author":"Yin","year":"2025","journal-title":"J. Bone Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Fhu, C.W., and Ali, A. (2020). Fatty acid synthase: An emerging target in cancer. Molecules, 25.","DOI":"10.3390\/molecules25173935"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"101342","DOI":"10.1016\/j.xcrm.2023.101342","article-title":"Decoupling NAD+ metabolic dependency in chondrosarcoma by targeting the SIRT1\u2013HIF-2\u03b1 axis","volume":"5","author":"Suh","year":"2024","journal-title":"Cell Rep. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4622","DOI":"10.1038\/s41467-019-12525-7","article-title":"Integrated molecular characterization of chondrosarcoma reveals critical determinants of disease progression","volume":"10","author":"Nicolle","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1038\/s42003-024-05790-w","article-title":"A single-cell atlas of conventional central chondrosarcoma reveals the role of endoplasmic reticulum stress in malignant transformation","volume":"7","author":"Su","year":"2024","journal-title":"Commun. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"eaap9840","DOI":"10.1126\/scitranslmed.aap9840","article-title":"Squalene epoxidase drives NAFLD-induced hepatocellular carcinoma and is a pharmaceutical target","volume":"10","author":"Liu","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2253","DOI":"10.1136\/gutjnl-2021-325851","article-title":"Squalene epoxidase drives cancer cell proliferation and promotes gut dysbiosis to accelerate colorectal carcinogenesis","volume":"71","author":"Li","year":"2022","journal-title":"Gut"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Zhang, L., Cao, Z., Hong, Y., He, H., Chen, L., Yu, Z., and Gao, Y. (2024). Squalene epoxidase: Its regulations and links with cancers. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25073874"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1172\/JCI0215593","article-title":"SREBPs: Activators of the complete program of cholesterol and fatty acid synthesis in the liver","volume":"109","author":"Horton","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/S0092-8674(00)80213-5","article-title":"The SREBP pathway: Regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor","volume":"89","author":"Brown","year":"1997","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1146\/annurev.biochem.70.1.341","article-title":"Peroxisome proliferator-activated receptor gamma and metabolic disease","volume":"70","author":"Willson","year":"2001","journal-title":"Annu. Rev. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Twenhafel, L., Moreno, D., Punt, T., Kinney, M., and Ryznar, R. (2023). Epigenetic changes associated with osteosarcoma: A comprehensive review. Cells, 12.","DOI":"10.3390\/cells12121595"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Cho, Y.J., Kim, S.H., Kim, E.K., Han, J.W., Shin, K.-H., Hu, H., Kim, K.S., Choi, Y.D., Kim, S., and Lee, Y.H. (2018). Prognostic implications of polycomb proteins EZH2, SUZ12, and EED1 and histone modification by H3K27me3 in sarcoma. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-4066-6"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1126\/science.1164097","article-title":"ATP-citrate lyase links cellular metabolism to histone acetylation","volume":"324","author":"Wellen","year":"2009","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4004","DOI":"10.1158\/1078-0432.CCR-16-2506","article-title":"Molecular pathways: Metabolic control of histone methylation and gene expression in cancer","volume":"23","author":"Tran","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1038\/nrc3929","article-title":"Hijacked in cancer: The KMT2 (MLL) family of methyltransferases","volume":"15","author":"Rao","year":"2015","journal-title":"Nat. Rev. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"38333","DOI":"10.18632\/oncotarget.9518","article-title":"Overexpression of EZH2 is associated with the poor prognosis in osteosarcoma and function analysis indicates a therapeutic potential","volume":"7","author":"Sun","year":"2016","journal-title":"Oncotarget"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1038\/s41571-021-00521-0","article-title":"The implications of IDH mutations for cancer development and therapy","volume":"18","author":"Pirozzi","year":"2021","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.ccr.2010.12.014","article-title":"Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of \u03b1-ketoglutarate-dependent dioxygenases","volume":"19","author":"Xu","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1186\/s13059-025-03812-2","article-title":"Loss of IDH1 and IDH2 mutations during the evolution of metastatic chondrosarcoma","volume":"26","author":"Cross","year":"2025","journal-title":"Genome Biol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Li, M., and Chen, C.-W. (2022). Epigenetic and transcriptional signaling in Ewing sarcoma. Biomedicines, 10.","DOI":"10.3390\/biomedicines10061325"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5307\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T07:01:09Z","timestamp":1781247669000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5307"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,11]]},"references-count":33,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27125307"],"URL":"https:\/\/doi.org\/10.3390\/ijms27125307","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,11]]}}}