IFN-γ-induced AIM2-PANoptosis in granulosa cells leads to ovulatory dysfunction in polycystic ovary syndrome

  • Biochem Pharmacol. 2026 Aug;250(Pt 2):118039. doi: 10.1016/j.bcp.2026.118039.
Qianjie Zhang  1 ,  Yicen Meng  1 ,  Weimin Zhao  2 ,  Wei Li  3 ,  Chaohui Dai  2 ,  Jinhua Cheng  2 ,  Bixia Li  2 ,  Fang Chen  2 ,  Jing Yang  4 ,  Hui Li  5 ,  Saijiao Li  6
Affiliations
  • 1. Reproductive Medical Center, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan 430060, China; Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Key Laboratory of Animal Breeding and Reproduction, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China; Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan 430060, China.
  • 2. Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Key Laboratory of Animal Breeding and Reproduction, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China; Jiangsu Provincial Engineering Research Center for Precision Animal Breeding, Nanjing 210014 China.
  • 3. Reproductive Medical Center, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan 430060, China.
  • 4. Reproductive Medical Center, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan 430060, China; Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan 430060, China.
  • 5. Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Key Laboratory of Animal Breeding and Reproduction, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China; Jiangsu Provincial Engineering Research Center for Precision Animal Breeding, Nanjing 210014 China; College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China. Electronic address: [email protected].
  • 6. Reproductive Medical Center, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan 430060, China; Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan 430060, China. Electronic address: [email protected].
PMID: 42114679 DOI: 10.1016/j.bcp.2026.118039
Abstract

Ovulatory dysfunction is a typical symptom of polycystic ovary syndrome (PCOS) and is widely recognized as a major obstacle to fertility. Numerous studies have reported a close association between the programmed cell death (PCD) of granulosa cells (GCs) and ovulatory dysfunction in PCOS. Recently, a novel type of PCD exhibiting features of Pyroptosis, Apoptosis, and Necroptosis was identified and termed PANoptosis. However, whether the PANoptosis occurs in PCOS GCs and plays a role in ovulatory dysfunction remains unclear. In this study, we found that the expression levels of PANoptosis-related molecules (NLRP3, CASP1, IL-1β, CASP3, MLKL), the PANoptosis regulator AIM2, IFN-γ, the IFN-responsive transcription factor 1 (IRF1), and HAS2 were significantly increased in GCs collected from PCOS patients, DHT-treated KGN cells, and the ovaries of DHEA-induced PCOS mouse models. Most importantly, KGN cells treated with a combination IFN-γ and lipopolysaccharide (LPS) exhibited similar effects. While, blocking IRF1 (using RNA interference-based knockdown), HAS2 (using 4-MU), JAK2 (using AZD-1480), or STAT3 (using SH-4-54) completely abolished these effects. Mechanistically, we revealed that elevated IFN-γ promotes AIM2 expression and AIM2-PANoptosome assembly through the JAK2/STAT3/IRF1/HAS2 axis. Further in vivo studies showed that inhibiting HAS2 (using 4-MU) and AIM2 (using A151) increased the number of oocytes retrieved from DHEA-induced PCOS mice. Taken together, our results suggest that AIM2-PANoptosis occurs in the GCs of PCOS and is triggered by the IFN-γ/IRF1/HAS2 signalling pathway, thereby resulting in ovulatory dysfunction. This study therefore provides valuable potential therapeutic targets for the treatment of this typical PCOS symptom.

Keywords
AIM2; Granulosa cell; HAS2; Ovulatory dysfunction; PANoptosis; PCOS.
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