2. Academic Validation
  3. SHP2 improves ovarian morphology and steroidogenic function in a rat PCOS model by modulating IRE1α/XBP1/NLRP3-mediated granulosa cell pyroptosis

SHP2 improves ovarian morphology and steroidogenic function in a rat PCOS model by modulating IRE1α/XBP1/NLRP3-mediated granulosa cell pyroptosis

  • Sci Rep. 2026 Mar 21;16(1):14376. doi: 10.1038/s41598-026-43536-2.
DongXue Wang 1,  JingNa Wang 1,  Bo Yang 2,  Xin Zhao 1,  Xiaoye Feng 1,  Qi Ding 2,  Yuanyuan Wu 1,  LiLi Bao 3
Affiliations

Affiliations

  • 1 Department of Reproduction and Genetics, Bethume International Peace Hospital, Shijiazhuang, 050000, China.
  • 2 Department of Obstetrics and Gynecology, Bethume International Peace Hospital, Shijiazhuang, 050000, China.
  • 3 Department of Reproduction and Genetics, Bethume International Peace Hospital, Shijiazhuang, 050000, China. [email protected].
PMID: 41865134 DOI: 10.1038/s41598-026-43536-2
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.

Supplementary Information: The online version contains supplementary material available at 10.1038/s41598-026-43536-2.

Keywords

IRE1α/XBP1/NLRP3; PCOS; SHP2; ZEB1/PKP3; granulosa cells.

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