Chronic inflammation in polycystic ovary syndrome (PCOS) worsens hormonal dysregulation, yet its precise molecular drivers in ovarian granulosa cells (GCs) have remained poorly defined. Using GCs from PCOS patients, LPS-treated KGN cells, and two mouse models (LPS-induced chronic inflammation and DHEA-induced PCOS), resveratrol (RES) treatment consistently suppressed elevated IL-6, IL-1β, MCP-1, and COX2 alongside the DNA-sensing inflammasome protein AIM2. Mechanistically, RES abolished LPS-induced JAK2/STAT3 phosphorylation; pharmacological JAK2/STAT3 blockade with AZD-1480 and SH-4-54 fully reversed AIM2 upregulation, establishing a causal JAK2/STAT3→AIM2 axis. In vivo, both RES and the AIM2 inhibitor A151 restored ovarian morphology and estrous cyclicity in DHEA-induced PCOS mice.
This study is noteworthy for identifying AIM2 — best known in innate immune surveillance of cytosolic DNA — as a downstream effector of JAK2/STAT3 in ovarian tissue, a mechanistic link not previously characterized in PCOS. It meaningfully advances beyond earlier resveratrol-PCOS studies that documented anti-inflammatory effects without mechanistic resolution. The multi-model convergence (human cells + two murine paradigms) strengthens biological plausibility. Practically, resveratrol's known bioavailability limitations remain a translational obstacle, and all efficacy data here are preclinical. The genuine clinical novelty lies in AIM2 as a druggable target — if validated in human trials, selective AIM2 inhibition could offer a precision strategy for PCOS inflammation independent of resveratrol's pharmacokinetic constraints. Incremental-to-significant in scope.
