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However, scalable methods to quantify inter-pathway crosstalk in RA remain lacking. To address this gap, we present MMP3C v2, an updated network-based framework that integrates gene expression with protein\u2013protein interaction network topology to compute directed pairwise metabolic plasticity (PMP) scores. We applied MMP3C v2 to ~3400 bulk transcriptomes (RA, osteoarthritis, systemic lupus erythematosus, and healthy controls) and\u2009~228\u2009000 single-cell transcriptomics from blood and synovium to profile RA-associated PMP alterations and develop diagnostic classifiers. We found that a single PMP-derived signature demonstrated strong predictive capability for diagnosis. Then, we developed a feature selection pipeline and combined it with 110 machine learning model combinations, by which we established the optimal ensemble classifier (stepwise forward selection + ridge regression), achieving robust and generalized performance (mean area under the curve (AUC)\u2009=\u20090.935; mean F1 score\u2009=\u20090.915) across 12 independent validation cohorts, outperforming seven previously published models. Single-cell analysis revealed cell-type-specific PMP remodeling: a Warburg-like shift in synovial macrophages (\u2191glycolysis, \u2191pentose phosphate pathway, \u2193oxidative phosphorylation). Cell\u2013cell communication analysis highlighted FN1-centered signaling linked to glucose metabolic remodeling in myofibroblasts. Collectively, MMP3C v2 establishes metabolic pathway crosstalk as a core diagnostic feature of RA, enabling interpretable and cross-platform diagnostic modeling and the identification of cell-type-specific PMP patterns. The open-source R package mmp3c supports reproducible analysis and broad application.<\/jats:p>","DOI":"10.1093\/bib\/bbag307","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T11:45:50Z","timestamp":1779363950000},"source":"Crossref","is-referenced-by-count":0,"title":["MMP3C v2: a network-based framework decoding metabolic plasticity in rheumatoid arthritis, enabling accurate diagnosis and uncovering cell-type-specific metabolic rewiring"],"prefix":"10.1093","volume":"27","author":[{"given":"Xingyu","family":"Chen","sequence":"first","affiliation":[{"name":"Dr. Neher\u2019s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Mechanism and Quality of Chinese Medicine & Faculty of Chinese Medicine, Macau University of Science and Technology , Avenida Wai Long, Taipa, Macau SAR 999078 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and Technology , Avenida Wai Long, Taipa, Macau SAR 999078 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naishu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Dr. Neher\u2019s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Mechanism and Quality of Chinese Medicine & Faculty of Chinese Medicine, Macau University of Science and Technology , Avenida Wai Long, Taipa, Macau SAR 999078 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Wu","sequence":"additional","affiliation":[{"name":"Dr. Neher\u2019s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Mechanism and Quality of Chinese Medicine & Faculty of Chinese Medicine, Macau University of Science and Technology , Avenida Wai Long, Taipa, Macau SAR 999078 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Laboratory for Innovative Drug Discovery, State Key Laboratory of Mechanism and Quality of Chinese Medicine & Faculty of Chinese Medicine, Macau University of Science and Technology , Avenida Wai Long, Taipa, Macau SAR 999078 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kit-Leong","family":"Cheong","sequence":"additional","affiliation":[{"name":"College of Food Science and Technology, Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Guangdong Province Engineering Laboratory for Marine Biological Products, Guangdong Provincial Engineering Technology Research Center of Seafood, Guangdong Provincial Engineering Technology Research Center of Prefabricated Seafood Processing and Quality Control, Guangdong Ocean University , No. 1 Haida Road, Mazhang District, Zhanjiang City, Guangdong Province 524088 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