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Despite affecting distinct tissues, these diseases exhibit a bidirectional association and converge on common immune-mediated mechanisms of bone resorption. To uncover the molecular drivers underlying bone destruction across inflammatory comorbidities, we combined bioinformatic analyses with experimental validation, using PD and RA as clinically relevant models of inflammatory disease comorbidities. Elevated blood lactate levels were observed in murine models of PD and RA and correlated positively with disease severity. Single-cell RNA sequencing data from PD and RA cohorts revealed upregulation of lactate metabolism-related genes in specific monocyte subsets, accompanied by enhanced pro-inflammatory signaling and osteoclastogenic programs. Using multiple machine learning approaches, SAT1, TET2 and HIF1A were identified as core lactate-related genes with strong diagnostic potential for both diseases. In vivo and in vitro experiments further validated that lactate-driven reprogramming of monocytes, marked by activation of core lactate-related genes in circulating monocytes and local macrophages, functionally connects immune activation with exacerbated bone resorption in comorbid PD and RA. Together, these findings define a lactate-driven immunometabolic axis connecting immune responses and bone remodeling and identify SAT1, TET2 and HIF1A as potential biomarkers for inflammation-related bone loss.<\/jats:p>","DOI":"10.3390\/biom16020308","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T12:37:28Z","timestamp":1771245448000},"page":"308","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lactate-Driven Reprogramming of Monocyte Bridges Bone Loss in Inflammatory Comorbidities"],"prefix":"10.3390","volume":"16","author":[{"given":"Junbin","family":"Wei","sequence":"first","affiliation":[{"name":"Hospital of Stomatology, Guanghua School of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7800-4209","authenticated-orcid":false,"given":"Zhiqian","family":"Ye","sequence":"additional","affiliation":[{"name":"Hospital of Stomatology, Guanghua School of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deqian","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Stomatology, The Fifth Affiliated Hospital of Sun Yat-sen University, 52 Meihua East Road, Xiangzhou District, Zhuhai 519000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manqing","family":"Liu","sequence":"additional","affiliation":[{"name":"Hospital of Stomatology, Guanghua School of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Botian","family":"Tan","sequence":"additional","affiliation":[{"name":"Hospital of Stomatology, Guanghua School of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9047-5163","authenticated-orcid":false,"given":"Houze","family":"Li","sequence":"additional","affiliation":[{"name":"Hospital of Stomatology, Guanghua School of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[{"name":"Hospital of Stomatology, Guanghua School of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8367-1851","authenticated-orcid":false,"given":"Qianmin","family":"Ou","sequence":"additional","affiliation":[{"name":"Hospital of Stomatology, Guanghua School of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"108635","DOI":"10.1016\/j.pharmthera.2024.108635","article-title":"Musculoskeletal crosstalk in chronic obstructive pulmonary disease and comorbidities: Emerging roles and therapeutic potentials","volume":"257","author":"Mou","year":"2024","journal-title":"Pharmacol. 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