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

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.