Resveratrol Alleviates Inflammation in Polycystic Ovary Syndrome by Inhibiting Absent in Melanoma 2 Expression

Since chronic inflammation is a typical feature of polycystic ovary syndrome (PCOS), both clinical and experimental studies have demonstrated that resveratrol (RES) can effectively alleviate it. However, the underlying mechanism remains unclear. To further investigate this, granulosa cells (GCs) derived from PCOS patients, lipopolysaccharide (LPS)-treated human granulosa cells (KGN), LPS-induced chronic inflammation mouse models, and dehydroepiandrosterone (DHEA)-induced PCOS mouse models were treated with RES. The expression of inflammatory cytokines, including interleukin (IL)-6, IL-1β, chemoattractant protein-1 (MCP-1), and cyclooxygenase-2 (COX2), as well as absent in melanoma 2 (AIM2), was examined. Additionally, ovarian morphological changes in these mouse models were assessed using hematoxylin-eosin (HE) staining. The results showed that the expression of these inflammatory cytokines and AIM2 increased significantly in GCs derived from PCOS patients and LPS-induced KGN cells, as well as in the ovaries of LPS-induced chronic inflammation and DHEA-induced PCOS mouse models. Furthermore, blocking AIM2 in LPS-treated KGN cells and mice with LPS-induced inflammation or PCOS significantly reduced the upregulation of inflammatory cytokines, similar to the results observed following RES treatment. In addition, LPS-induced phosphorylation of the JAK2/STAT3 pathway in KGN cells was completely abolished by RES treatment. Notably, LPS-induced upregulation of AIM2 and these inflammatory cytokines was completely reversed by blocking the JAK2/STAT3 pathway using AZD-1480 and SH-4-54, respectively. Further in vivo studies showed that ovarian morphological and estrous cycle disturbances in DHEA-induced PCOS mouse models were effectively ameliorated by RES and A151. In conclusion, RES alleviates chronic inflammation in PCOS by inhibiting AIM2 via blocking the JAK2/STAT3 pathway. Our findings suggest that the targeted inhibition of AIM2 could represent a novel therapeutic approach for PCOS.