Abstract
The specific role and mechanism of SHP2 in polycystic ovary syndrome (PCOS) remain unclear. This study aimed to evaluate the therapeutic potential of SHP2 and elucidate the signaling pathways through which it modulates granulosa cell fate in PCOS. A PCOS rat model was established via letrozole administration. Rats were divided into three groups (n = 6 each): Sham, Model, and SHP2-overexpressing (SHP2-OE). The SHP2-OE group received lentiviral injection prior to modeling. Ovarian histopathology was assessed using Hematoxylin and Eosin (HE) staining. Serum sex hormones were measured by ELISA. Western blotting was used to detect the protein expression of the IRE1α/XBP1/NLRP3 and ZEB1/PKP3 signaling pathways in granulosa cells after different stimulations. Flow cytometry was used to detect granulosa cell apoptosis. In vivo, SHP2 overexpression significantly ameliorated PCOS-induced ovarian damage, characterized by reduced ovarian weight, fewer cystic follicles, and increased corpora lutea. Hormonally, SHP2-OE decreased levels of estradiol, testosterone, and luteinizing hormone, while increasing follicle-stimulating hormone. Mechanistically, in vitro analysis revealed that testosterone treatment inhibited SHP2 phosphorylation and downregulated PKP3, nuclear E2F1, and CyclinB1. In addition to addition, testosterone activated the IRE1α/XBP1/NLRP3 and ZEB1 pathways, upregulating p-IRE1α, XBP-1s, p-SP1, ZEB1, NLRP3, and GSDMD, thereby promoting granulosa cell apoptosis and pyroptosis. SHP2 alleviates PCOS-related reproductive endocrine abnormalities and ovarian pathological changes by regulating the IRE1α/XBP1/NLRP3 and ZEB1/PKP3 signaling pathways, thereby influencing granulosa cell pyroptosis and proliferation.
Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Fund name: Scientific Research Fund of Hebei Provincial Health and Family Planning Commission. Fund title: Empty follicle syndrome: genetic factors, pathogenesis and prognosis analysis. Fund No.: 20231289.
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L.L.B wrote the first draft of the manuscript. D.X.W and J.N.W ‘s main work is data collection and analysis. B.Y and X.Z are responsible for bioinformatics analysis and statistical analysis. X.Y.F was in charge of the experimental part of the manuscript. Q.D and Y.Y.W was in charge of the revision of the manuscript. All authors have reviewed the manuscript.
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This study was approved by the Medical Ethics Committee of the 980th Hospital of the Joint Logistics and Security Force of the Chinese People’s Liberation Army. (Approval number: 2022-KY-59).
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Wang, D., Wang, J., Yang, B. et al. SHP2 improves ovarian morphology and steroidogenic function in a rat PCOS model by modulating IRE1α/XBP1/NLRP3-mediated granulosa cell pyroptosis. Sci Rep (2026). https://doi.org/10.1038/s41598-026-43536-2
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DOI: https://doi.org/10.1038/s41598-026-43536-2
