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Targeting p38 MAPK signaling pathway: 
Quercetin as a novel therapy for TMJ synovitis

  • Authors:
    • Mosha Cheng
    • Yuhe Guan
    • Xiaotao Xin
    • Xin Yi
    • Yi Liu
  • View Affiliations / Copyright

    Affiliations: Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning 110002, P.R. China, Department of Stomatology, First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China, Department of Oral Anatomy and Physiology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning 110002, P.R. China, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning 110002, P.R. China
    Copyright: © Cheng et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 4.0].
  • Article Number: 21
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    Published online on: November 13, 2025
       https://doi.org/10.3892/ijmm.2025.5692
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Abstract

Temporomandibular joint (TMJ) synovitis is a chronic inflammatory condition prevalent in temporoman-dibular disorders, characterized by synovial inflammation and bone degradation. Quercetin, a natural flavonoid with diverse bioactive properties, is investigated for its potential in ameliorating TMJ synovitis by targeting the p38 MAPK pathway. Using network pharmacology and in vitro and in vivo models, the effects of quercetin on synoviocytes and inflammatory responses were evaluated. Results showed quercetin's significant inhibition of synoviocyte proliferation, promotion of apoptosis and reduction of inflammatory cytokines. Moreover, quercetin demonstrated stability in binding to critical targets like MAPK14 and led to downregulation of phosphorylated p38 MAPK and JNK. In vivo, quercetin improved synovial tissue architecture and mitigated bone destruction. Mechanistic studies confirmed the dependency of effects of quercetin on the p38 MAPK pathway, supported by functional experiments using pathway agonists and inhibitors. The present study underscored the potential of quercetin in treating TMJ synovitis by modulating inflammatory signaling, promoting cell apoptosis and preserving bone integrity, thereby offering novel insights into therapeutic strategies for TMJ‑related synovitis.
View Figures

Figure 1

Network pharmacology analysis reveals
key signaling pathways and core target genes of quercetin in
synovitis. (A) Schematic workflow of network pharmacology analysis
for identifying core targets; (B) 2D chemical structure of
quercetin; (C) A total of 95 potential therapeutic targets were
identified by intersecting quercetin-predicted targets with
synovitis and TMJ disorder-related disease targets; (D) PPI network
of the 95 targets constructed using the STRING database. Node size
and color represent the degree of connectivity; (E) Top 10 hub
genes identified by the MCC algorithm, including MAPK14, MMP13 and
IL6. TMJ, temporomandibular joint; PPI, protein-protein
interaction; MCC, maximal clique centrality; MMP, matrix
metalloproteinase.

Figure 2

Identifying key signaling pathways
and MF enrichment patterns associated with quercetin in synovitis.
(A) GO enrichment analysis of potential of quercetin targets,
showing the top 15 markedly enriched terms across three categories:
BP, MF and CC; (B) KEGG pathway enrichment analysis of the
predicted targets, displaying the top 15 markedly enriched
signaling pathways. Notably, the IL-17, MAPK, TNF and PI3K-Akt
pathways were among the most markedly enriched, suggesting that
quercetin may exert anti-synovitis effects by modulating these
inflammation-related pathways. GO, Gene Ontology; BP, Biological
Process; MF, Molecular Function; CC, Cellular Component; KEGG,
Kyoto Encyclopedia of Genes and Genomes.

Figure 3

Molecular docking validation of
quercetin binding to key targets in the MAPK and IL-17 signaling
pathways. Binding modes of quercetin with (A) MMP3, (B) MMP9, (C)
MMP13, (D) MAPK1, (E) MAPK8 and (F) MAPK14. Each panel illustrates
the complex's three-dimensional structure, the protein's
electrostatic surface and the two-dimensional interaction map of
the protein-ligand complex.

Figure 4

MD simulations evaluate the binding
stability of quercetin with key target proteins. (A and B) The RMSD
changes of each complex within 100 ns were evaluated to assess
their overall structural stability; (C and D) RMSF analysis showing
flexibility variations of individual protein residues; (E and F)
Time-dependent changes in the number of hydrogen bonds, reflecting
the physical stability of ligand binding; (G and H) Rg analysis
assessing the compactness of protein structures. The results
demonstrate that quercetin forms stable complexes with MMP and MAPK
family targets. MD, Molecular Dynamics; RMSD, root-mean-square
deviation; RMSF, root-mean-square fluctuation; Rg, radius of
gyration; MMP, matrix metalloproteinase.

Figure 5

Evaluation of the regulatory effects
of quercetin on synovial cell proliferation, apoptosis and
inflammatory cytokine expression under inflammatory stimulation.
(A) Schematic diagram of the in vitro experimental workflow.
(B) CCK-8 assay showing the proliferation activity of SW982
synoviocytes after treatment with various concentrations of
quercetin (0-100 μM) for 24 h. (C and D) Annexin V/7-AAD
dual-staining flow cytometry analysis of apoptosis, demonstrating a
concentration-dependent increase in apoptotic rate. All experiments
were performed in triplicate (n=3) and data are presented as mean ±
SD. Statistical comparisons between groups were conducted using
one-way ANOVA. Significance levels vs. the 0 μM group are
indicated as: *P<0.05, **P<0.01,
***P<0.001; ns: insignificant. CCK-8, Cell Counting
Kit-8.

Figure 6

Multi-level validation of
quercetin-mediated regulation of inflammatory cytokines and MMPs
via inhibition of the p38 MAPK signaling pathway. (A) ELISA
analysis showing the effects of different concentrations of
quercetin on IL-1β-induced secretion of MMP3, MMP9 and MMP13 in
SW982 cells; (B) Western blot analysis of TNF-α, IL-1β and IL-6
protein expression levels, with β-tubulin as the internal control;
(C and D) Western blot analysis of phosphorylation levels of key
MAPK signaling molecules: p38, ERK1/2 and JNK; (E) Quantitative
analysis of phosphorylated proteins, showing that quercetin
markedly inhibited the expression of p-p38 and p-JNK, with no
significant effect on p-ERK1/2. All experiments were independently
repeated three times (n=3) and data are presented as mean ± SD.
Statistical comparisons were performed using one-way ANOVA.
Significance levels compared with the model group or 0 μM
group are indicated as: *P<0.05,
**P<0.01, ***P<0.001; ns:
insignificant. MMPs, matrix metalloproteinases; ELISA,
enzyme-linked immunosorbent assay; p-, phosphorylated.

Figure 7

Multi-level analysis validates
quercetin's therapeutic effects on synovitis and its regulatory
role in inflammation-related signaling pathways. (A) H&E
staining assessing changes in synovial structure and inflammatory
cell infiltration. (B) Safranin O-Fast Green staining showing
alterations in proteoglycan distribution in condylar cartilage. (C)
Dual immunofluorescence staining analyzing the co-localization of
p-p38 MAPK (green) with IL-6 (red) and MMP13 (red) in synovial
tissue. (D) qPCR analysis of key gene expression levels, including
MAPK14, MAPKAPK2, DUSP1, IL-6, TNF-α and MMP13, in SW982 cells and
synovial tissues. All histological experiments were conducted with
five animals per group (n=5) and molecular experiments were
independently repeated three times (n=3). Data are presented as
mean ± SD. Statistical comparisons were performed using one-way
ANOVA. Significance levels: *P<0.05,
**P<0.01, ***P<0.001,
****P<0.0001; ns, insignificant. H&E, hematoxylin
and eosin; MMP, matrix metalloproteinase; qPCR, quantitative
PCR.

Figure 8

Quercetin alleviates inflammatory
cytokine expression and mitigates bone destruction by modulating
the p38 MAPK signaling pathway. (A) InstantOne ELISA analysis of
p-p38 MAPK, p-JNK and p-ERK levels in synovial tissue. (B) IHC
staining showing expression changes of MMP13, IL-6 and p-p38 MAPK
in synovial tissue. (C) Evaluation of subchondral bone destruction
using Micro-CT sagittal slices, (D and E) 3D reconstructions and
(F) cylindrical ROI of rat condylar bone. (G) Quantitative analysis
of BV/TV, Tb.N and Tb.Sp. Scale bar, 500 μm. Comparisons
were made against the CFA group. Each group included five rats
(n=5) and data are presented as mean ± SD. Statistical analysis was
performed using one-way ANOVA; *P<0.05,
**P<0.01, ***P<0.001. ELISA,
enzyme-linked immunosorbent assay; p-, phosphorylated; IHC,
immunohistochemistry; MMP, matrix metalloproteinase; Micro-CT,
micro-computed tomography; ROI, region of interest; BV/TV, bone
volume/tissue volume; Tb.N, trabecular number; Tb.Sp, trabecular
separation; CFA, Complete Freund's Adjuvant.

Figure 9

Agonist/inhibitor experiments confirm
that the anti-inflammatory mechanism of quercetin depends on the
p38 MAPK signaling pathway. (A) Western blot analysis of p-p38 MAPK
protein expression. (B) ELISA detection of IL-6 and TNF-α secretion
levels (pg/ml). (C) CCK-8 assay for evaluating cell proliferation
activity (OD450). (D) Annexin V/PI flow cytometry analysis of
apoptosis rate (%). Experimental groups included: Control, IL-1β,
IL-1β + quercetin, IL-1β + quercetin + SB203580 and IL-1β +
quercetin + anisomycin. All experiments were independently repeated
three times (n=3) and data are expressed as mean ± SD. Statistical
comparisons were performed using one-way ANOVA;
*P<0.05, **P<0.01,
***P<0.001 ****P<0.0001; ns:
insignificant. p-, phosphorylated; ELISA, enzyme-linked
immunosorbent assay; CCK-8, Cell Counting Kit-8; OD, optical
density.
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Copy and paste a formatted citation
Spandidos Publications style
Cheng M, Guan Y, Xin X, Yi X and Liu Y: Targeting p38 MAPK signaling pathway:&nbsp;<br />Quercetin as a novel therapy for TMJ synovitis. Int J Mol Med 57: 21, 2026.
APA
Cheng, M., Guan, Y., Xin, X., Yi, X., & Liu, Y. (2026). Targeting p38 MAPK signaling pathway:&nbsp;<br />Quercetin as a novel therapy for TMJ synovitis. International Journal of Molecular Medicine, 57, 21. https://doi.org/10.3892/ijmm.2025.5692
MLA
Cheng, M., Guan, Y., Xin, X., Yi, X., Liu, Y."Targeting p38 MAPK signaling pathway:&nbsp;<br />Quercetin as a novel therapy for TMJ synovitis". International Journal of Molecular Medicine 57.1 (2026): 21.
Chicago
Cheng, M., Guan, Y., Xin, X., Yi, X., Liu, Y."Targeting p38 MAPK signaling pathway:&nbsp;<br />Quercetin as a novel therapy for TMJ synovitis". International Journal of Molecular Medicine 57, no. 1 (2026): 21. https://doi.org/10.3892/ijmm.2025.5692
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Spandidos Publications style
Cheng M, Guan Y, Xin X, Yi X and Liu Y: Targeting p38 MAPK signaling pathway:&nbsp;<br />Quercetin as a novel therapy for TMJ synovitis. Int J Mol Med 57: 21, 2026.
APA
Cheng, M., Guan, Y., Xin, X., Yi, X., & Liu, Y. (2026). Targeting p38 MAPK signaling pathway:&nbsp;<br />Quercetin as a novel therapy for TMJ synovitis. International Journal of Molecular Medicine, 57, 21. https://doi.org/10.3892/ijmm.2025.5692
MLA
Cheng, M., Guan, Y., Xin, X., Yi, X., Liu, Y."Targeting p38 MAPK signaling pathway:&nbsp;<br />Quercetin as a novel therapy for TMJ synovitis". International Journal of Molecular Medicine 57.1 (2026): 21.
Chicago
Cheng, M., Guan, Y., Xin, X., Yi, X., Liu, Y."Targeting p38 MAPK signaling pathway:&nbsp;<br />Quercetin as a novel therapy for TMJ synovitis". International Journal of Molecular Medicine 57, no. 1 (2026): 21. https://doi.org/10.3892/ijmm.2025.5692
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