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While PIK3CA-induced metabolic reprogramming elevates lactate levels, the role of histone lactylation in FIL pathogenesis remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Adipose stem and progenitor cells (ASPCs) from FIL adipose tissue were isolated. Glycolysis inhibitors (2-DG, oxamate), lactate supplementation, and siRNA-mediated knockdown were used to modulate lactylation. CUT&amp;Tag sequencing, Western blot, qPCR, ChIP-qPCR and functional assays (osteogenic\/adipogenic differentiation) were performed to elucidate the potential mechanism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>FIL-ASPCs exhibited hyperlactylation, particularly at H3K18. H3K18la promoted osteogenesis by activating osteogenic genes, while adipogenesis remained unaffected. Inhibition of lactylation via glycolysis inhibitors or LDHA\/LDHB knockdown suppressed osteogenic differentiation, whereas lactate supplementation reversed these effects. TGF-\u03b21 stimulation could increase lactylation levels and promote osteogenic differentiation. Moreover, H3K18la upregulated hexokinase 2 (HK2), enhancing glycolysis and lactate production, thereby forming a lactate-H3K18la-HK2 positive feedback loop.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study identified H3K18 lactylation as a key epigenetic driver of FIL-associated osseous hyperplasia via a lactate-H3K18la-HK2 feedback loop. Targeting this axis may offer therapeutic potential for FIL and related metabolic bone disorders.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13287-025-04651-5","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T09:41:17Z","timestamp":1759311677000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["H3K18 lactylation-hexokinase 2 positive feedback loop promotes osteogenesis of ASPCs in facial infiltrating lipomatosis"],"prefix":"10.1186","volume":"16","author":[{"given":"Hongrui","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Hua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Jen","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajing","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxi","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,1]]},"reference":[{"issue":"6","key":"4651_CR1","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1111\/pde.15346","volume":"40","author":"H Chen","year":"2023","unstructured":"Chen H, et al. 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Written informed consent forms were signed by patients or patients\u2019 parents whose facial adipose sample were collected in this study. Title of the approved project: Treatment and mechanism of Pl3K\/mTOR dual-target inhibitor (WX390) on PlK3CA-related overgrowth spectrum (PROS). Date of approval: 06, October, 2022. All animal procedures were performed following protocols approved by the Institutional Animal Care and Use Committee (IACUC) of the Shanghai Jiao Tong University School of Medicine (SH9H-2022-A916-1). Title of the approved project: Etiological Research on Limb Developmental Defects and Construction of a Precision Prevention and Treatment System: Research on the Pathogenesis and Targeted Therapy of Limb Proliferative Diseases Caused by Somatic Activating Mutations. Date of approval: 11, November, 2022.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The consent for publication was acquired from patients\u2019 parents. All authors confirm their consent for publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"538"}}