Acetylation reader BRD4-driven TXNIP transcription enhances NLRP3 inflammasome activation in PCOS.

Polycystic ovary syndrome (PCOS) is an endocrine disorder characterized by the developmental arrest and dysfunction of ovarian granulosa cells (GCs), serving as a major cause of infertility among women of reproductive age. Persistent activation of thioredoxin-interacting protein (TXNIP) due to aberrant histone acetylation modifications of transcription is a potential trigger; however, its precise upstream regulatory mechanism remains poorly understood. In this study, we found that TXNIP was aberrantly upregulated in both the dehydroepiandrosterone (DHEA)-induced PCOS-like rat model and the dihydrotestosterone (DHT)-induced primary GCs PCOS-like model in vitro. The TXNIP/NLRP3 inhibitor ruscogenin and the small interfering RNA (siRNA) targeting TXNIP remarkably inhibited NLRP3 inflammasome activation, subsequently reversing aberrant reproductive and metabolic phenotypes in PCOS-like models. Further bioinformatic analysis revealed that the promoter region of TXNIP contains binding motifs of bromodomain-containing protein 4 (BRD4) and androgen receptor (AR). BRD4 and AR exhibited inducible binding to the histone H3 acetylation-enriched TXNIP promoter, whereas intervention with the BRD4-selective inhibitor JQ1 and the AR-selective inhibitor attenuated this binding, leading to subsequent downregulation of TXNIP transcription that ultimately resulted in NLRP3 inflammasome suppression. Our data indicate that BRD4 upregulation and the resultant TXNIP transcriptional activation are crucial regulatory pathways for NLRP3 inflammasome activation, resulting in associated reproductive and metabolic abnormalities in ovarian GCs from PCOS.