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Recent advances in single-cell and spatial omics, together with immunometabolic studies, have revealed marked state heterogeneity among synovial macrophages in RA. Their metabolic reprogramming appears to sustain pathogenic cellular states, drive aberrant intercellular communication and impair the resolution of inflammation. Rather than acting as an independent initiating factor, it more likely operates as a downstream amplifier of disease. In this review, we outline the principal functional states and metabolic features of synovial macrophages in health and RA. We focus on how the rewiring of glucose, lipid and amino acid metabolism links inflammatory transcription, tissue remodelling and bone destruction. These connections are mediated by metabolic enzymes, metabolic intermediates, redox regulation and epigenetic modifications. We further summarise the immunometabolic effects of currently available antirheumatic drugs. We also appraise the preclinical evidence and translational limitations of metabolic pathway inhibitors, natural products and nanodelivery systems. It should be noted that most existing evidence still relies on in vitro polarisation systems and rodent models. Validation of metabolic flux, cell-state specificity and causal relationships in human synovium remains limited. As a narrative review focused on recent studies of synovial macrophage metabolism in health and inflammation, this work aims to delineate how metabolic reprogramming shapes the phenotypic heterogeneity and pathogenic functions of macrophages in RA. It also seeks to appraise the potential value and current boundaries of evidence for therapeutically targeting macrophage metabolism.<\/jats:p>","DOI":"10.3390\/cells15131166","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:54:42Z","timestamp":1782694482000},"page":"1166","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Macrophage Metabolic Reprogramming in Rheumatoid Arthritis: Pathogenic Mechanisms and Therapeutic Implications"],"prefix":"10.3390","volume":"15","author":[{"given":"Longping","family":"Chen","sequence":"first","affiliation":[{"name":"School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha 410208, China"},{"name":"School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyuan","family":"Leng","sequence":"additional","affiliation":[{"name":"Institute of Innovation and Applied Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junlan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Innovation and Applied Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute of Innovation and Applied Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyu","family":"Hu","sequence":"additional","affiliation":[{"name":"Institute of Innovation and Applied Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4644-4451","authenticated-orcid":false,"given":"Xiong","family":"Cai","sequence":"additional","affiliation":[{"name":"Institute of Innovation and Applied Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1016\/S0140-6736(16)30173-8","article-title":"Rheumatoid arthritis","volume":"388","author":"Smolen","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/s41572-020-0168-y","article-title":"Rheumatoid arthritis Primer\u2014Behind the scenes","volume":"6","author":"Smolen","year":"2020","journal-title":"Nat. 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