{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T21:02:04Z","timestamp":1792443724184,"version":"4.5.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study aimed to systematically identify key differentially expressed genes (DEGs) associated with lysine lactylation in osteoporosis and to explore their potential roles in disease pathogenesis from a dual perspective of metabolic and immune regulation, thereby providing a theoretical basis for targeted therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Five osteoporosis-related gene expression microarray datasets and one single-cell RNA-sequencing dataset were integrated from the GEO database. A lactylation-related gene panel comprising 1,347 genes was used to construct a screening framework. Batch effect correction, differential expression analysis, GO\/KEGG enrichment, CIBERSORT-based immune infiltration, and GSEA\/GSVA functional annotation were performed. A total of 113 combinations of machine learning models were applied to identify key genes. Single-cell UMAP clustering and CellChat-based intercellular communication analysis were conducted to further characterize the findings.\n                      <jats:italic>In vitro<\/jats:italic>\n                      experiments were performed using RAW264.7 macrophages treated with lactate and osteoporotic serum, and gene expression and lactylation levels were validated via qPCR, Western blot, and co-immunoprecipitation (Co-IP).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 37 lactylation-related DEGs were identified, mainly enriched in metabolic and inflammatory pathways. Among them,\n                      <jats:italic>AKR1A1<\/jats:italic>\n                      was highlighted as a key feature gene through machine learning models, exhibiting elevated expression and high levels of lactylation, particularly enriched in monocytes and macrophages. CellChat analysis revealed that\n                      <jats:italic>AKR1A1<\/jats:italic>\n                      participates in the\n                      <jats:italic>SPP1\u2013CD44<\/jats:italic>\n                      signaling pathway, mediating intercellular communication among immune cells.\n                      <jats:italic>In vitro<\/jats:italic>\n                      validation confirmed that\n                      <jats:italic>AKR1A1<\/jats:italic>\n                      expression and lactylation levels were significantly upregulated under combined lactate and osteoporotic serum treatment, suggesting a synergistic enhancement effect.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      <jats:italic>AKR1A1<\/jats:italic>\n                      lactylation plays a pivotal role in the metabolic\u2013immune regulatory axis of osteoporosis, contributing to metabolic reprogramming and immune microenvironment remodeling. Through involvement in the\n                      <jats:italic>SPP1\u2013CD44<\/jats:italic>\n                      signaling pathway, it mediates communication between monocytes and macrophages, and may serve as a novel biomarker and therapeutic target for early diagnosis and intervention in osteoporosis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1680305","type":"journal-article","created":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T06:23:19Z","timestamp":1761805399000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Lactylation-related gene AKR1A1 contributes to osteoporosis via metabolic\u2013immune regulation: evidence from multi-omics integration, single-cell transcriptomics, and in vitro validation"],"prefix":"10.3389","volume":"16","author":[{"given":"Zichen","family":"Shao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinqin","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfeng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weikang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weidong","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"29493","DOI":"10.1038\/s41598-024-80993-z","article-title":"Single-cell RNA sequencing reveals multiple immune cell subpopulations promote the formation of abnormal bone microenvironment in osteoporosis","volume":"14","author":"Yang","year":"2024","journal-title":"Sci Rep"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.882241","article-title":"The global burden of osteoporosis, low bone mass, and its related fracture in 204 countries and territories, 1990-2019","volume":"13","author":"Shen","year":"2022","journal-title":"Front endocrinology"},{"key":"B3","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1186\/s12891-023-06865-1","article-title":"Clinicians\u2019 views of prescribing oral and intravenous bisphosphonates for osteoporosis: a qualitative study","volume":"24","author":"ishop","year":"2023","journal-title":"BMC musculoskeletal Disord"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3390\/jcm12010014","article-title":"Non-adherence to anti-osteoporosis medication: factors influencing and strategies to overcome it. 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