ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Cellular Biochemistry
Volume 13 - 2025 | doi: 10.3389/fcell.2025.1658089
This article is part of the Research TopicMechanism Study of Bioactive Molecules Using Omics TechnologyView all 5 articles
Specific inhibition of glutamine synthase involved in the metabolic pathway of amino acids is associated with anti-arthritic effects of sinomenine hydrochloride
Provisionally accepted
- 1Hunan University of Chinese Medicine, Changsha, China
- 2The First Hospital of Hunan University of Chinese Medicine, Changsha, China
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Sinomenine is the key bioactive alkaloid isolated from Sinomenium acutum which has been prescribed commonly in Chinese medicine for managing rheumatic disorders. Despite its clinical relevance, the metabolic mechanisms underlying its therapeutic effects remain insufficiently explored, particularly in relation to amino acid dysregulation in rheumatoid arthritis (RA).The anti-arthritic efficacy of SH was tested in adjuvant-induced arthritis in rats utilizing clinical scoring and histological analysis. Plasma metabolomics was employed to identify SH-mediated changes in amino acid-related metabolic profiles. Key metabolic pathways and targets were examined using computational docking and surface plasmon resonance (SPR) assay. The interaction of SH and molecular targets was further validated in RA fibroblast-like synoviocytes (RA-FLS). SH at dose of 100 mg/kg significantly alleviated disease progression of AIA, as evidenced by reduced paw edema and inhibited histopathological changes. Metabolomic analyses identified 94 potential plasma biomarkers linked to pathways of valine/leucine/isoleucine biosynthesis, glycine/serine/threonine metabolism, phenylalanine metabolism, and alanine/aspartate/glutamate metabolism. Molecular docking and SPR identified that SH specifically targeted the glutamine synthase (GS/GLUL) (KD=7.12 μM). Experimental validation confirmed that SH (50-200 μM) significantly inhibited GS activity and GLUL expression and consequently decreased glutamine levels in RA-FLS. In conjunction SH exerts significant anti-arthritic effects, partly by modulating the metabolic profiles of related amino acids via selective inhibition of GS-mediated de novo Gln synthesis.
Keywords: Rheumatoid arthritis, Sinomenine hydrochloride, Metabolomics, Adjuvantinduced arthritis, glutamine synthetase
Received: 02 Jul 2025; Accepted: 14 Aug 2025.
Copyright: © 2025 Li, Su, Tang, Huang, Zhang, Lin, Zhang and Cai. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Xiong Cai, Hunan University of Chinese Medicine, Changsha, China
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