Integrated Network Toxicology, Molecular Dynamics Simulation and In Vitro Assays Identify EGFR, ESR1 and IGF1 as Core Mediators of Bisphenol S-Exacerbated Polycystic Ovary Syndrome
5 affiliations
- 1Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control, Beijing 100013, China
- 2School of Public Health, Capital Medical University, Beijing 100069, China
- 3School of Agricultural Sciences, Zhengzhou University, Zhengzhou 450001, China
- 4Biology and Agriculture Research Center, University of Science and Technology Beijing, Beijing 100083, China
- 5Medical College, Shaoxing University, Shaoxing 312000, China
Abstract
Bisphenol S (BPS), an environmental endocrine disruptor, has been implicated in polycystic ovary syndrome (PCOS), but its underlying molecular targets remain largely uncharacterized. Here, this study integrated network toxicology, molecular simulations and in vitro cellular assays to identify key mediators of BPS-associated PCOS. A total of 199 overlapping target genes between BPS exposure and PCOS were screened from public databases, predicted hub genes were extracted via protein–protein interaction (PPI) network construction and 30 core hub genes were enriched in oxidative stress, hormone response, inflammation, cell-cycle regulation, and PI3K-Akt, FoxO, AGE-RAGE, and endocrine resistance pathways by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Using molecular docking simulations found that the top 15 hub proteins exhibited favorable binding affinities for BPS, with binding free energies below −5.0 kcal/mol. Molecular dynamics simulations revealed that BPS binding induced only minor conformational perturbations in EGFR and ESR1, with negligible effects on backbone stability, core domain flexibility, global compactness and surface properties. In contrast, BPS association effectively dampened global backbone fluctuations and the residue-level mobility of IGF1, and the intermolecular hydrogen bond strength followed the order IGF1 > EGFR > ESR1. In KGN cells, BPS suppressed cell viability and proliferation in a time- and dose-dependent manner while upregulating the protein levels of EGFR, ESR1 and IGF1; notably, IGF1 was most sensitive to low-dose BPS exposure. These findings suggest that BPS may exacerbate PCOS progression by upregulating EGFR, ESR1 and IGF1 to inhibit granulosa cell growth, and thereby disrupt ovarian oxidative homeostasis, hormone signaling, insulin metabolism and cell-cycle regulation via the PI3K-Akt and FoxO pathways. This study provides a theoretical framework for assessing the reproductive health risks of BPS, and lays a foundation for further experimental validation and population-based epidemiological research.
Related
- Investigating potential molecular mechanisms linking 6PPD-quinone exposure to Intervertebral Disc Degeneration: A network toxicology, molecular docking, and molecular dynamics simulation study
- Exploring the mechanism of 6PPD/6PPD-Q-induced allergic rhinitis based on network toxicology, molecular docking, and molecular dynamic simulation
- BDE-47 and male infertility: integrated network toxicology, single-cell transcriptomics, and in vitro evidence of GSTM1 downregulation and ferroptosis-related molecular remodeling in Leydig cells.
- Integrated network toxicology, transcriptomic, and Mendelian randomization analyses explore potential molecular links between acrylamide exposure and clear cell renal cell carcinoma.
- Revealing the toxicological effects and mechanisms of tris(1-chloro-2-propyl) phosphate exposure on osteoarthritis based on network toxicology, machine learning, and molecular docking
BibTeX
@article{liu2026integrated,
title = {{Integrated Network Toxicology, Molecular Dynamics Simulation and In Vitro Assays Identify EGFR, ESR1 and IGF1 as Core Mediators of Bisphenol S-Exacerbated Polycystic Ovary Syndrome}},
author = {Juan Liu and Guolin Ye and Xin Liu and Zhongyuan Deng and Yeling Ma},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27208961},
url = {https://www.mdpi.com/1422-0067/27/20/8961},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Integrated Network Toxicology, Molecular Dynamics Simulation and In Vitro Assays Identify EGFR, ESR1 and IGF1 as Core Mediators of Bisphenol S-Exacerbated Polycystic Ovary Syndrome
AU - Juan Liu
AU - Guolin Ye
AU - Xin Liu
AU - Zhongyuan Deng
AU - Yeling Ma
PY - 2026
DA - 2026/10/09
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27208961
UR - https://www.mdpi.com/1422-0067/27/20/8961
AB - Bisphenol S (BPS), an environmental endocrine disruptor, has been implicated in polycystic ovary syndrome (PCOS), but its underlying molecular targets remain largely uncharacterized. Here, this study integrated network toxicology, molecular simulations and in vitro cellular assays to identify key mediators of BPS-associated PCOS. A total of 199 overlapping target genes between BPS exposure and PCOS were screened from public databases, predicted hub genes were extracted via protein–protein interaction (PPI) network construction and 30 core hub genes were enriched in oxidative stress, hormone response, inflammation, cell-cycle regulation, and PI3K-Akt, FoxO, AGE-RAGE, and endocrine resistance pathways by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Using molecular docking simulations found that the top 15 hub proteins exhibited favorable binding affinities for BPS, with binding free energies below −5.0 kcal/mol. Molecular dynamics simulations revealed that BPS binding induced only minor conformational perturbations in EGFR and ESR1, with negligible effects on backbone stability, core domain flexibility, global compactness and surface properties. In contrast, BPS association effectively dampened global backbone fluctuations and the residue-level mobility of IGF1, and the intermolecular hydrogen bond strength followed the order IGF1 > EGFR > ESR1. In KGN cells, BPS suppressed cell viability and proliferation in a time- and dose-dependent manner while upregulating the protein levels of EGFR, ESR1 and IGF1; notably, IGF1 was most sensitive to low-dose BPS exposure. These findings suggest that BPS may exacerbate PCOS progression by upregulating EGFR, ESR1 and IGF1 to inhibit granulosa cell growth, and thereby disrupt ovarian oxidative homeostasis, hormone signaling, insulin metabolism and cell-cycle regulation via the PI3K-Akt and FoxO pathways. This study provides a theoretical framework for assessing the reproductive health risks of BPS, and lays a foundation for further experimental validation and population-based epidemiological research.
SN - 1422-0067
ER -