miR-761-hepcidin/Gpx4 pathway contribute to unexplained liver dysfunction in polycystic ovary syndrome by regulating liver iron overload and ferroptosis

Aims: To investigate the underling mechanisms of liver dysfunction in patients with polycystic ovary syndrome (PCOS).Materials and methods: PCOS patients were enrolled according to the Amsterdam criteria while PCOS animal model was established by dihydrotestosterone (DHEA) sustained release tablet implantation on its neck. Further liver damage and iron overload were detected by HE and Prussian blue staining. The liver related enzymes, mRNA and protein levels of hepcidin and GPX4 were tested by ELISA, qRT-PCR and Western blot. RNA interference and miR-761 transfection were routinely performed while the regulation of miR-761 on hepcidin and GPX4 was confirmed by luciferase reporter gene analysis.Results: We found that a part of PCOS patients and animal model had unexplained liver damage, which is independent of nonalcoholic fatty liver disease (NAFLD) and accompanied by increased ferrum (Fe) deposition. Besides, the expression of hepcidin and GPX4 that is important effector proteins for ferroptosis was down regulated in liver, showing the importance of iron metabolism in this unexplained liver damage. Based on the miR-761-hepcidin/GPX4 axis, we systematically studied the effects of miR-761 on ferroptosis and Fe deposition, which further influence the phenotype and liver function of PCOS model. From both in vivo and in vitro levels, changes in PCOS disease phenotype and ferroptosis were observed through hierarchical antagonism or overexpression of miR-761, hepcidin and GPX4.Conclusions: our results provide a novel explanation for unexplained liver damage in PCOS and a potential therapeutic target.