{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:31:46Z","timestamp":1790728306102,"version":"4.1.0"},"reference-count":42,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:00:00Z","timestamp":1770249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Discipline and Platform Construction Project of the Science and Technology Innovation Project, Chinese Academy of Traditional Chinese Medicine","award":["KYG-202409"],"award-info":[{"award-number":["KYG-202409"]}]},{"name":"Science and Technology Innovation Project of the China Academy of Chinese Medical Sciences","award":["CI2021A0O108"],"award-info":[{"award-number":["CI2021A0O108"]}]},{"name":"Independent Topic Selection Research Project of the Institute of Basic Theory of Chinese Medicine, China Academy of Chinese Medical Sciences","award":["YZX-202232"],"award-info":[{"award-number":["YZX-202232"]}]},{"name":"National Natural Science Foundation of China Youth Program","award":["81403282"],"award-info":[{"award-number":["81403282"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Rheumatoid arthritis involves chronic synovitis and immune-metabolic dysregulation, highlighting a need for multi-target therapies that jointly modulate metabolism and inflammation. We developed glycyrrhiza protein\u2013paeoniflorin self-assembled nanoparticles (GP-PF NPs) and investigated their anti-arthritic mechanism in adjuvant-induced arthritis (AIA) mice, using UHPLC-Orbitrap-MS-based metabolomics. Male C57BL\/6 mice (n = 42) were assigned to the control, model, GP-PF NPs, paeoniflorin, glycyrrhiza protein, physical mixture, and celecoxib groups. All groups except controls received complete Freund\u2019s adjuvant, and treatments were given intraperitoneally for 10 days. GP-PF NPs produced the greatest reduction in paw thickness versus the model (p &lt; 0.0001) and outperformed all other active treatments, which was consistent with the improved histopathology. UHPLC-Orbitrap-MS detected 473 serum metabolites, and the model group showed 59 significant changes versus the control. GP-PF NPs significantly modulated 108 metabolites and yielded robust OPLS-DA separation from the model (R2Y = 0.98; Q2 = 0.742). Venn and pathway analyses identified 43 NP-specific metabolites enriched in glycerophospholipid metabolism, including glycerophosphocholine, 1-oleylglycerophosphocholine, PE (16:0\/16:0), phosphocholine, and sphingosine-1-phosphate. These metabolites were selectively normalized toward control levels by GP-PF NPs. qPCR further showed that GP-PF NPs significantly reduced synovial PI3K, AKT, mTOR, NLRP3, Caspase-1, and GSDMD mRNA overexpression (all p &lt; 0.001 vs. model). Correlation analysis indicated significant associations between key serum lipids and synovial genes (e.g., PI3K positively correlated with several metabolites, r = 0.71\u20130.82; mTOR negatively correlated with sphinganine 1-phosphate and glycerophosphocholine, r = \u22120.65 and \u22120.54). These data suggest that GP-PF NPs ameliorate AIA and are associated with the normalization of glycerophospholipid-related metabolic perturbations and reduced synovial mRNA expression of the PI3K\/AKT\/mTOR-NLRP3 pathway, supporting their potential as a metabolism-inflammation preclinical oriented anti-arthritic nanomedicine.<\/jats:p>","DOI":"10.3390\/molecules31030554","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T11:13:01Z","timestamp":1770289981000},"page":"554","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A UHPLC-Orbitrap-MS Metabolomics Strategy Reveals Glycerophospholipid Metabolic Remodeling Is Associated with the Anti-Arthritic Effect of Glycyrrhiza Protein\u2013Paeoniflorin Nanoparticles via PI3K\/AKT\/NLRP3 Axis"],"prefix":"10.3390","volume":"31","author":[{"given":"Na","family":"Zhang","sequence":"first","affiliation":[{"name":"Institute of Basic Theory of Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyun","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Basic Theory of Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cui","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Basic Theory of Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaoxin","family":"Huo","sequence":"additional","affiliation":[{"name":"Institute of Basic Theory of Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Gao","sequence":"additional","affiliation":[{"name":"Institute of Basic Theory of Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Bai","sequence":"additional","affiliation":[{"name":"Institute of Basic Theory of Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqin","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Basic Theory of Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,5]]},"reference":[{"key":"ref_1","first-page":"1707","article-title":"Pathogenesis of rheumatoid arthritis: One year in review 2024","volume":"42","author":"Cirillo","year":"2024","journal-title":"Clin. 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