Isoquercetin Attenuates Graves’ Disease-Related Thyroid Epithelial Inflammatory Responses: Exploratory Evidence from Network Pharmacology, Mendelian Randomization, and Cellular Validation
- 1Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, People’s Republic of China
Abstract
Background: Graves’ disease (GD) is initiated by thyroid-stimulating hormone receptor autoantibody signaling, whereas cytokine-mediated inflammation within the thyroid may amplify thyrocyte activation. The microbiota-related metabolites contributing to this inflammatory component remain incompletely defined.
Methods: We integrated reported gut microbiota–metabolite associations with GD-associated genes, constructed protein–protein interaction and enrichment networks, prioritized candidate metabolites, and evaluated predicted docking of isoquercetin (ISO) with inflammatory targets. Two-sample Mendelian randomization (MR) used MiBioGen microbiota and FinnGen autoimmune hyperthyroidism data. A separate four-group experiment compared control, M22 alone, interferon-γ (IFN-γ) alone, and combined M22/IFN-γ stimulation in Nthy-ori 3–1 thyroid follicular epithelial cells. ISO treatment was then evaluated under combined stimulation; inflammatory transcripts, NF-κB p65 phosphorylation, and cell viability were assessed.
Results: Fifty-three shared targets were identified, and the highest-degree PPI nodes included IL6, TNF, AKT1, IL1B, JUN, NFKB1, TP53, and CASP3. The shared targets were enriched in TNF, NF-κB, MAPK, PI3K-Akt, and Th17-related pathways. After chemical-name standardization, ISO had a network degree of 8 and was connected with TNF and IL6; docking indicated predicted molecular compatibility rather than direct binding. Twelve taxa showed nominal IVW associations with GD, but none survived false discovery rate correction. In the four-group experiment, IFN-γ was the dominant stimulus for IL1B, IL6, and TNF expression; the combined M22/IFN-γ group had the highest mean expression, but no interaction term was significant. Under combined stimulation, ISO reduced inflammatory transcripts and the phospho-p65/total p65 ratio without markedly changing total p65.
Conclusion: These exploratory, convergent findings identify ISO as a microbiota-related candidate modulator of thyroid epithelial inflammatory responses. They do not establish microbial production, direct target binding, or clinical efficacy, and require further mechanistic and in vivo validation.
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BibTeX
@article{zhang2026isoquercetin,
title = {{Isoquercetin Attenuates Graves’ Disease-Related Thyroid Epithelial Inflammatory Responses: Exploratory Evidence from Network Pharmacology, Mendelian Randomization, and Cellular Validation}},
author = {Shihan Zhang and Qunwei Ma and Xiaoyu Ding and Xinzhong Zhang and Guang Wang and Jia Liu},
journal = {Journal of Inflammation Research},
year = {2026},
month = oct,
doi = {10.2147/jir.s643441},
url = {https://doi.org/10.2147/jir.s643441},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Isoquercetin Attenuates Graves’ Disease-Related Thyroid Epithelial Inflammatory Responses: Exploratory Evidence from Network Pharmacology, Mendelian Randomization, and Cellular Validation
AU - Shihan Zhang
AU - Qunwei Ma
AU - Xiaoyu Ding
AU - Xinzhong Zhang
AU - Guang Wang
AU - Jia Liu
PY - 2026
DA - 2026/10/30
JO - Journal of Inflammation Research
DO - 10.2147/jir.s643441
UR - https://doi.org/10.2147/jir.s643441
AB - Background: Graves’ disease (GD) is initiated by thyroid-stimulating hormone receptor autoantibody signaling, whereas cytokine-mediated inflammation within the thyroid may amplify thyrocyte activation. The microbiota-related metabolites contributing to this inflammatory component remain incompletely defined. Methods: We integrated reported gut microbiota–metabolite associations with GD-associated genes, constructed protein–protein interaction and enrichment networks, prioritized candidate metabolites, and evaluated predicted docking of isoquercetin (ISO) with inflammatory targets. Two-sample Mendelian randomization (MR) used MiBioGen microbiota and FinnGen autoimmune hyperthyroidism data. A separate four-group experiment compared control, M22 alone, interferon-γ (IFN-γ) alone, and combined M22/IFN-γ stimulation in Nthy-ori 3–1 thyroid follicular epithelial cells. ISO treatment was then evaluated under combined stimulation; inflammatory transcripts, NF-κB p65 phosphorylation, and cell viability were assessed. Results: Fifty-three shared targets were identified, and the highest-degree PPI nodes included IL6, TNF, AKT1, IL1B, JUN, NFKB1, TP53, and CASP3. The shared targets were enriched in TNF, NF-κB, MAPK, PI3K-Akt, and Th17-related pathways. After chemical-name standardization, ISO had a network degree of 8 and was connected with TNF and IL6; docking indicated predicted molecular compatibility rather than direct binding. Twelve taxa showed nominal IVW associations with GD, but none survived false discovery rate correction. In the four-group experiment, IFN-γ was the dominant stimulus for IL1B, IL6, and TNF expression; the combined M22/IFN-γ group had the highest mean expression, but no interaction term was significant. Under combined stimulation, ISO reduced inflammatory transcripts and the phospho-p65/total p65 ratio without markedly changing total p65. Conclusion: These exploratory, convergent findings identify ISO as a microbiota-related candidate modulator of thyroid epithelial inflammatory responses. They do not establish microbial production, direct target binding, or clinical efficacy, and require further mechanistic and in vivo validation.
SN - 1178-7031
ER -