Journal of Inflammation Research (Feb 2025)
Quercetin, a Compound of the Total Flavonoids of Periploca forrestii Schltr., Ameliorates Rheumatoid Arthritis by Targeting TNF-α
Abstract
Shuaishuai Chen,1,2,* Weina Xue,1,3,* Zhongxiu Wu,4,* Dingyan Lu,1 Lin Zheng,1,5 Meng Zhou,1 Yongjun Li,1,5 Yonglin Wang,1,3 Ting Liu1 1State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Guizhou Medical University, Guian New Area, 561113, People’s Republic of China; 2Guizhou Institute of Precision Medicine, Affiliated Hospital of Guizhou Medical University, Guiyang, 550009, People’s Republic of China; 3School of Pharmacy, Guizhou Medical University, Guian New Area, 561113, People’s Republic of China; 4Department of Pharmacy, Zhejiang Provincial People’s Hospital Bijie Hospital, Bijie, 551799, People’s Republic of China; 5National Engineering Research Center of Miao’s Medicines, Guiyang, 550004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yongjun Li; Ting Liu, State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Guizhou Medical University, 6, Ankang Avenue, Guian New Area, 561113, People’s Republic of China, Tel +86 0851-86908468, Email [email protected]; [email protected]: The total flavonoids of Periploca forrestii Schltr. (TFPF) exhibit notable anti-rheumatoid arthritis (RA) properties, highlighted by their inhibitory action on TNF-α. This study investigates the specific compounds of TFPF responsible for TNF-α inhibition and delineates their mechanism of action.Methods: L929 cells and luciferase-based assays were used to assess anti-TNF-α activity. Additionally, MH7A cells and Wistar rats were employed to establish in vitro and in vivo models of RA. Chemical chromatography, thermal proteome profiling (TPP), molecular docking, surface plasmon resonance (SPR), cellular thermal shift assays (CETSA), drug affinity responsive target stability tests (DARTS), and transcriptomic analysis were used to study the potent molecules of TFPF and their protein targets and pathways. H&E staining, immunofluorescence staining, ELISA, and Western blot were employed for pharmacodynamic and mechanism studies of these potent molecules.Results: TFPF mitigated cellular injury in L929 cells and inhibited luciferase expression, both of which were induced by TNF-α. Among the eight compounds identified, quercetin exhibited the most potent anti-TNF-α activity. Quercetin improved cellular injury and reduced the cell apoptosis rate in L929 cells treated with TNF-α. TPP revealed the interaction between quercetin and TNF-α, which was verified by molecular docking, SPR, CETSA, and DARTS assays. Transcriptomic analysis highlighted the TNF signaling pathway, suggesting that quercetin may target TNF-α to inhibit the activation of the NF-κB signaling pathway. Quercetin inhibited luciferase expression, suppressed the phosphorylation of IκBα and p65, blocked p65 nuclear translocation, and reduced the mRNA expression of COX-2, INOS, IL-6, and IL-1β. Moreover, quercetin decreased inflammation and joint damage in RA.Conclusion: Quercetin, a compound of TFPF, interacts with and inhibits the activity of TNF-α, thereby suppressing the TNF-α/NF-κB signaling pathway and alleviating the symptoms of RA. These findings position quercetin as a promising TNF-α inhibitor for the treatment of RA. Keywords: TNF-α inhibitor, quercetin, total flavonoids of Periploca forrestii Schltr., rheumatoid arthritis, molecular interaction techniques, binding ability
