Guizhi-Shaoyao-Zhimu decoction attenuates rheumatoid arthritis partially by reversing inflammation-immune system imbalance.
Guizhi-Shaoyao-Zhimu decoction (GSZD) has been extensively used for rheumatoid arthritis (RA) therapy. Marked therapeutic efficacy of GSZD acting on RA has been demonstrated in several long-term clinical trials without any significant side effects. However, its pharmacological mechanisms remain unclear due to a lack of appropriate scientific methodology.



GSZD's mechanisms of action were investigated using an integrative approach that combined drug target prediction, network analysis, and experimental validation.



A total of 77 putative targets were identified for 165 assessed chemical components of GSZD. After calculating the topological features of the nodes and edges in the created drug-target network, we identified a candidate GSZD-targeted signal axis that contained interactions between two putative GSZD targets [histone deacetylase 1 (HDAC1) and heat shock protein 90 kDa alpha, class A member 1 (HSP90AA1)] and three known RA-related targets [NFKB2; inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta (IKBKB); and tumor necrosis factor-alpha (TNF-α)]. This signal axis could connect different functional modules that are significantly associated with various RA-related signaling pathways, including T/B cell receptor, Toll-like receptor, NF-kappa B and TNF pathways, as well as osteoclast differentiation. Furthermore, the therapeutic effects and putative molecular mechanisms of GSZD's actions on RA were experimentally validated in vitro and in vivo.



GSZD may partially attenuate RA by reversing inflammation-immune system imbalance and regulating the HDAC1-HSP90AA1-NFKB2-IKBKB-TNF-α signaling axis.
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
Qiuyan
Q
Guo
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
Xia
X
Mao
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China. yqzhang@icmm.ac.cn.
Yanqiong
Y
Zhang
Department of Pathology, Beijing Jishuitan Hospital, Peking University, Beijing, 100035, China.
Shuqin
S
Meng
Department of Pathology, Beijing Jishuitan Hospital, Peking University, Beijing, 100035, China.
Yue
Y
Xi
Department of Pathology, Beijing Jishuitan Hospital, Peking University, Beijing, 100035, China.
Yi
Y
Ding
School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Hubei, 430070, China.
Xiaocun
X
Zhang
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
Yuntao
Y
Dai
School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Hubei, 430070, China.
Xia
X
Liu
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
Chao
C
Wang
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
Yuting
Y
Li
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China. linna888@163.com.
Na
N
Lin
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology*; D018450:Disease Progression; D004359:Drug Therapy, Combination; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use*; D007107:Immune System / Q000187:drug effects / Q000473:pathology*; D007249:Inflammation / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D007596:Joints / Q000187:drug effects / Q000473:pathology; D008297:Male; D011917:Rats, Inbred Lew; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D013585:Synovitis / Q000188:drug therapy / Q000473:pathology
D004365:Drugs, Chinese Herbal; C000605452:guizhi-shaoyao-zhimu decoction
Experimental validation; Guizhi-Shaoyao-Zhimu decoction; Network pharmacology; Rheumatoid arthritis; TCM herbal formula