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Although clinicians routinely prioritize glycemic control before initiating implant-related treatment plans, diabetic patients often exhibit impaired osseointegration. However, the specific mechanisms remain to be elucidated. Emerging evidence suggests that this refractory bone loss is mediated by trained immunity, a process in which innate immune cells retain an epigenetic memory of prior inflammatory stimuli and mount an exaggerated response upon secondary challenge such as the invasive implantation process or inflammatory insult. Here, integrating RNA-seq, metabolomics, and transposase-accessible chromatin using sequencing analyses, we demonstrate that stringent glycemic control in type 1 diabetes fails to normalize the fatty acid biosynthetic process, which remains persistently activated and potentiates macrophage-mediated inflammation and osteoclastogenesis when experiencing the secondary stimuli. Mechanistically, prior hyperglycemic exposure enhances chromatin accessibility while sustaining\n                    <jats:italic toggle=\"yes\">Acsl1<\/jats:italic>\n                    transcription by H3K4me1 epigenetic modification at the\n                    <jats:italic toggle=\"yes\">Acsl1<\/jats:italic>\n                    locus in macrophages. This epigenetic imprint augments fatty acid anabolism, amplifies proinflammatory cytokine production, and accelerates osteoclastic differentiation, ultimately compromising osseous repair. Collectively, our findings reveal that diabetes-induced H3K4me1 modification at\n                    <jats:italic toggle=\"yes\">Acsl1<\/jats:italic>\n                    drives metabolic reprogramming underpinning trained immunity and consequent bone damage. Targeting H3K4me1 or\n                    <jats:italic toggle=\"yes\">Acsl1<\/jats:italic>\n                    therefore represents a promising therapeutic strategy to improve implant osseointegration and skeletal regeneration in diabetic patients.\n                  <\/jats:p>","DOI":"10.1177\/00220345261430286","type":"journal-article","created":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T09:00:18Z","timestamp":1774688418000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Acsl1-Mediated Fatty Acid Synthesis Impairs Osseointegration in Type 1 Diabetes"],"prefix":"10.1177","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-6551-1201","authenticated-orcid":false,"given":"X.H.","family":"Zheng","sequence":"first","affiliation":[{"name":"The Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X.Y.","family":"Zhu","sequence":"additional","affiliation":[{"name":"The Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3928-1598","authenticated-orcid":false,"given":"X.","family":"Chen","sequence":"additional","affiliation":[{"name":"The Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6019-7664","authenticated-orcid":false,"given":"Q.Q.","family":"He","sequence":"additional","affiliation":[{"name":"The Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0947-722X","authenticated-orcid":false,"given":"Q.M.","family":"Zhai","sequence":"additional","affiliation":[{"name":"The Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5658-5525","authenticated-orcid":false,"given":"T.","family":"Chen","sequence":"additional","affiliation":[{"name":"The Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,3,28]]},"reference":[{"key":"e_1_3_2_2_1","doi-asserted-by":"crossref","unstructured":"Al Ansari Y Shahwan H Chrcanovic BR. 2022. Diabetes mellitus and dental implants: a systematic review and meta-analysis. Materials. 15(9):3227. https:\/\/doi.org\/10.3390\/ma15093227","DOI":"10.3390\/ma15093227"},{"key":"e_1_3_2_3_1","doi-asserted-by":"crossref","unstructured":"Al-Rashed F et al. 2023. ACSL1 is a key regulator of inflammatory and macrophage foaming induced by short-term palmitate exposure or acute high-fat feeding. iScience. 26(7):107145. https:\/\/doi.org\/10.1016\/j.isci.2023.107145","DOI":"10.1016\/j.isci.2023.107145"},{"key":"e_1_3_2_4_1","doi-asserted-by":"crossref","unstructured":"Andersson R Sandelin A. 2020. Determinants of enhancer and promoter activities of regulatory elements. Nat Rev Genet. 21(2):71\u201387. https:\/\/doi.org\/10.1038\/s41576-019-0173-8","DOI":"10.1038\/s41576-019-0173-8"},{"key":"e_1_3_2_5_1","doi-asserted-by":"crossref","unstructured":"Bostr\u00f6m P et al. 2006. Hypoxia converts human macrophages into triglyceride-loaded foam cells. Arterioscler Thromb Vasc Biol. 26(8):1871\u20131876. https:\/\/doi.org\/10.1161\/01.atv.0000229665.78997.0b","DOI":"10.1161\/01.ATV.0000229665.78997.0b"},{"key":"e_1_3_2_6_1","doi-asserted-by":"crossref","unstructured":"Braun T Schett G. 2012. Pathways for bone loss in inflammatory disease. Curr Osteoporos Rep. 10(2):101\u2013108. https:\/\/doi.org\/10.1007\/s11914-012-0104-5","DOI":"10.1007\/s11914-012-0104-5"},{"key":"e_1_3_2_7_1","doi-asserted-by":"crossref","unstructured":"Castoldi A et al. 2020. Triacylglycerol synthesis enhances macrophage inflammatory function. Nat Commun. 11(1):4107. https:\/\/doi.org\/10.1038\/s41467-020-17881-3","DOI":"10.1038\/s41467-020-17881-3"},{"key":"e_1_3_2_8_1","doi-asserted-by":"crossref","unstructured":"Chalmers J Cooper ME. 2008. UKPDS and the legacy effect. N Engl J Med. 359(15):1618\u20131620. https:\/\/doi.org\/10.1056\/nejme0807625","DOI":"10.1056\/NEJMe0807625"},{"key":"e_1_3_2_9_1","doi-asserted-by":"crossref","unstructured":"Del Cuore A et al. 2023. Metabolic memory in diabetic foot syndrome (DFS): MICRO-RNAs single nucleotide polymorphisms (SNPs) frequency and their relationship with indices of endothelial function and adipo-inflammatory dysfunction. Cardiovasc Diabetol. 22(1):148. https:\/\/doi.org\/10.1186\/s12933-023-01880-x","DOI":"10.1186\/s12933-023-01880-x"},{"key":"e_1_3_2_10_1","doi-asserted-by":"crossref","unstructured":"Edgar L et al. 2021. Hyperglycemia induces trained immunity in macrophages and their precursors and promotes atherosclerosis. Circulation. 144(12):961\u2013982. https:\/\/doi.org\/10.1161\/circulationaha.120.046464","DOI":"10.1161\/CIRCULATIONAHA.120.046464"},{"key":"e_1_3_2_11_1","doi-asserted-by":"crossref","unstructured":"Eming SA Murray PJ Pearce EJ. 2021. 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