The role of PLAU in polycystic ovary syndrome: activation of STAT3-mediated NLRP3 signaling to promote granulosa cell injury, inflammation, and apoptosis

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder. Granulosa cell dysfunction is an important factor causing PCOS.PLAU has been shown to be upregulated in granulosa cells of PCOS patients, but its potential mechanism in regulating the progression of PCOS has not been clarified. The present study focused on the mechanisms by which PLAU regulates granulosa cell injury and apoptosis in PCOS. Establishment of a testosterone-induced granulosa cell model. Flow cytometry was performed to test granulosa cell viability and apoptosis. RT-qPCR was applied to measure the mRNA levels of hormone synthesis related genes. The expressions of PLAU, STAT3, and NLRP3 inflammasome as well as apoptosis-related proteins were assessed by western blot. Binding between STAT3 and NLRP3 was detected using ChIP-PCR assay. Inhibitors and agonists of STAT3 were utilized to validate the role of PLAU and STAT3 signaling in testosterone-treated granulosa cells. Upregulation of PLAU, STAT3, and NLRP3 signaling was observed in testosterone-treated granulosa cells. Both PLAU interference and STAT3 inhibitors inhibited testosterone-induced granulosa cell viability, impaired function injured, inflammation, and apoptosis. Additionally, downregulation of PLAU decreased STAT3 and NLRP3 levels. Further results showed that STAT3 bound to the NLRP3 promoter. STAT3 agonists partially counteracted the ameliorative effect of PLAU knockdown on testosterone-induced granulosa cell dysfunction. These results suggest that downregulated PLAU may improve testosterone-induced granulosa cell dysfunction by inhibiting STAT3/NLRP3 signaling, providing a new molecular mechanism for PCOS progression.