Andrographolide sulfonate alleviates rheumatoid arthritis by inhibiting glycolysis-mediated activation of PI3K/AKT to restrain Th17 cell differentiation.
10.1016/S1875-5364(25)60855-7
- Author:
Chunhong JIANG
1
;
Xi ZENG
2
;
Jia WANG
1
;
Xiaoqian WU
2
;
Lijuan SONG
2
;
Ling YANG
2
;
Ze LI
2
;
Ning XIE
3
;
Xiaomei YUAN
1
;
Zhifeng WEI
4
;
Yi GUAN
5
Author Information
1. Guangdong-Hong Kong Joint Laboratory for Emerging Infectious Diseases, Joint Institute of Virology (Shantou University and The University of Hong Kong), Shantou University Medical College, Shantou 515041, China.
2. Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 210009, China.
3. State Key Laboratory of Innovative Natural Medicine and TCM Injection, Ganzhou 341000, China.
4. Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 210009, China. Electronic address: 1020132346@cpu.edu.cn.
5. Guangdong-Hong Kong Joint Laboratory for Emerging Infectious Diseases, Joint Institute of Virology (Shantou University and The University of Hong Kong), Shantou University Medical College, Shantou 515041, China; State Key Laboratory of Emerging Infectious Diseases (SKLEID), School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. Electronic address: yguan@hku.hk.
- Publication Type:Journal Article
- Keywords:
Andrographolide sulfonate;
Glycolysis;
PI3K/AKT pathway;
Rheumatoid arthritis;
Th17 cell differentiation
- MeSH:
Animals;
Th17 Cells/immunology*;
Diterpenes/pharmacology*;
Arthritis, Rheumatoid/metabolism*;
Proto-Oncogene Proteins c-akt/immunology*;
Glycolysis/drug effects*;
Cell Differentiation/drug effects*;
Phosphatidylinositol 3-Kinases/genetics*;
Rats;
Male;
Rats, Sprague-Dawley;
Humans;
Andrographis paniculata/chemistry*;
Arthritis, Experimental/drug therapy*;
Interleukin-17/immunology*;
Signal Transduction/drug effects*
- From:
Chinese Journal of Natural Medicines (English Ed.)
2025;23(4):480-491
- CountryChina
- Language:English
-
Abstract:
Andrographolide sulfonate (AS) is a sulfonated derivative of andrographolide extracted from Andrographis paniculata (Burm.f.) Nees, and has been approved for several decades in China. The present study aimed to investigate the novel therapeutic application and possible mechanisms of AS in the treatment of rheumatoid arthritis. Results indicated that administration of AS by injection or gavage significantly reduced the paw swelling, improved body weights, and attenuated pathological changes in joints of rats with adjuvant-induced arthritis. Additionally, the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1β in the serum and ankle joints were reduced. Bioinformatics analysis, along with the spleen index and measurements of IL-17 and IL-10 levels, suggested a potential relationship between AS and Th17 cells under arthritic conditions. In vitro, AS was shown to block Th17 cell differentiation, as evidenced by the reduced percentages of CD4+ IL-17A+ T cells and decreased expression levels of RORγt, IL-17A, IL-17F, IL-21, and IL-22, without affecting the cell viability and apoptosis. This effect was attributed to the limited glycolysis, as indicated by metabolomics analysis, reduced glucose uptake, and pH measurements. Further investigation revealed that AS might bind to hexokinase2 (HK2) to down-regulate the protein levels of HK2 but not glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or pyruvate kinase M2 (PKM2), and overexpression of HK2 reversed the inhibition of AS on Th17 cell differentiation. Furthermore, AS impaired the activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signals in vivo and in vitro, which was abolished by the addition of lactate. In conclusion, AS significantly improved adjuvant-induced arthritis (AIA) in rats by inhibiting glycolysis-mediated activation of PI3K/AKT to restrain Th17 cell differentiation.
