Total glucosides of paeony alleviates cGAS-STING-mediated diseases by blocking the STING-IRF3 interaction

Ye XIU; Sihao WANG; Ping ZHANG; Chengwei LI; Zhixin WU; Jincai WEN; Yingjie XU; Guiji LV; Xiaomei ZHAO; Xu DONG; Yichong CHEN; Junjie LI; Yan WANG; Liang ZOU; Xiaohe XIAO; Zhaofang BAI

doi:10.1016/S1875-5364(24)60572-8

Chinese Journal of Natural Medicines ›› 2024, Vol. 22 ›› Issue (5) :402 -415. DOI: 10.1016/S1875-5364(24)60572-8

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research-article

Total glucosides of paeony alleviates cGAS-STING-mediated diseases by blocking the STING-IRF3 interaction

Ye XIU ¹^,²^,³^,^∆
, Sihao WANG ²^,³^,^∆
, Ping ZHANG ⁴^,^∆
, Chengwei LI ¹^,²^,³
, Zhixin WU ²^,³
, Jincai WEN ²^,³
, Yingjie XU ²^,³
, Guiji LV ²^,³
, Xiaomei ZHAO ²^,³
, Xu DONG ²^,³
, Yichong CHEN ¹
, Junjie LI ²^,³
, Yan WANG ²^,³
, Liang ZOU ⁵^,^*
, Xiaohe XIAO ¹^,²^,³^,⁶^,^*
, Zhaofang BAI ¹^,²^,³^,⁶^,^*

Author information +

¹ School of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China

² Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing 100039, China

³ China Military Institute of Chinese Materia, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China

⁴ Department of Pharmacy, Medical Supplies Center of PLA General Hospital, Beijing 100039, China

⁵ School of Food and Biological Engineering, Chengdu University, Chengdu 610106, China

⁶ National Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing 100039, China

^* E-mails: zouliangcdu@126.com (ZOU Liang);

pharmacy_302@126.com (XIAO Xiaohe);

baizf2008@hotmail.com (BAI Zhaofang)

ZOU Liang: Professor Liang Zou is the Director of the Science and Technology Department at Chengdu University.He is one of the leading scientists in the Molecular Pharmacology and Biopharmacy Laboratory at Chengdu University. He has been working in the field of naturally derived bioactives and nanomedicines for approximately 20 years, with his current research focusing on the pharmacological effects of active ingredients from Traditional Chinese Medicine.

XIAO Xiaohe: Prof. Xiaohe Xiao is the director of Academic Committee of Senior Department of Hepatology of the Fifth Medical Center of Chinese PLA General Hospital, and director of China Military Institute of Chinese Materia Medica, with the professional and technical rank of Major General. He is the recipient of the National Science Fund for Distinguished Young Scholars, one of the first batch of National Qihuang Scholars, the National Ten Outstanding Youths of Traditional Chinese Medicine.

BAI Zhaofang: Prof. Bai Zhaofang is the director of the Institute of Department of Hepatology of the Fifth Medical Center of Chinese PLA General Hospital，the vice director of China Military Institute of Chinese Materia Medica, and reserve academic leader of National Key Discipline of clinical traditional Chinese pharmacy. He mainly engages in research on the immunopharmacology and immunotoxicology of Traditional Chinese Medicine.

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Abstract

In the realm of autoimmune and inflammatory diseases, the cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) signaling pathway has been thoroughly investigated and established. Despite this, the clinical approval of drugs targeting the cGAS-STING pathway has been limited. The Total glucosides of paeony (TGP) is highly anti-inflammatory and is commonly used in the treatment of rheumatoid arthritis (RA), emerged as a subject of our study. We found that the TGP markedly reduced the activation of the cGAS-STING signaling pathway, triggered by various cGAS-STING agonists, in mouse bone marrow-derived macrophages (BMDMs) and Tohoku Hospital Pediatrics-1 (THP-1) cells. This inhibition was noted alongside the suppression of interferon regulatory factor 3 (IRF3) phosphorylation and the expression of interferon-beta (IFN-β), C-X-C motif chemokine ligand 10 (CXCL10), and inflammatory mediators such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). The mechanism of action appeared to involve the TGP’s attenuation of the STING-IRF3 interaction, without affecting STING oligomerization, thereby inhibiting the activation of downstream signaling pathways. In vivo, the TGP hindered the initiation of the cGAS-STING pathway by the STING agonist dimethylxanthenone-4-acetic acid (DMXAA) and exhibited promising therapeutic effects in a model of acute liver injury induced by lipopolysaccharide (LPS) and D-galactosamine (D-GalN). Our findings underscore the potential of the TGP as an effective inhibitor of the cGAS-STING pathway, offering a new treatment avenue for inflammatory and autoimmune diseases mediated by this pathway.

Keywords

Total glucosides of gaeony / cGAS-STING pathway / Inflammation / LPS/D-GalN / STING inhibitor

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Ye XIU, Sihao WANG, Ping ZHANG, Chengwei LI, Zhixin WU, Jincai WEN, Yingjie XU, Guiji LV, Xiaomei ZHAO, Xu DONG, Yichong CHEN, Junjie LI, Yan WANG, Liang ZOU, Xiaohe XIAO, Zhaofang BAI. Total glucosides of paeony alleviates cGAS-STING-mediated diseases by blocking the STING-IRF3 interaction. Chinese Journal of Natural Medicines, 2024, 22(5): 402-415 DOI:10.1016/S1875-5364(24)60572-8

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