Hyperandrogenemia Induces Trophoblast Ferroptosis and Early Pregnancy Loss in Patients With PCOS via CMA‐Dependent FTH1 Degradation

Polycystic ovary syndrome (PCOS) patients with hyperandrogenemia exhibit an increased risk of early pregnancy loss; however, the underlying mechanisms remain poorly understood. Ferroptosis, an iron-dependent form of cell death driven by phospholipid peroxidation, has been implicated in various diseases. This study identifies significant iron homeostasis disorders and ferroptosis in PCOS patients with hyperandrogenemia, which is mediated by androgen-induced reduction of ferritin heavy chain 1 (FTH1) protein levels in trophoblasts. Specifically, androgens upregulate FTH1 mRNA and protein synthesis by binding to androgen response elements on the FTH1 promoter via the androgen receptor (AR). Simultaneously, elevated androgen levels enhance chaperone-mediated autophagy (CMA) through upregulating LAMP2A (lysosomal-associated membrane protein 2), thereby promoting FTH1 protein degradation. When androgen levels are excessive or AR is overactivated, this CMA-driven degradation exceeds FTH1 protein synthesis, leading to a reduction in FTH1 level. Furthermore, metformin was found to compete with androgens for AR binding, thereby stabilizing FTH1 and protecting trophoblasts from ferroptosis. In PCOS-model mice, metformin significantly reduced early embryonic absorption. These findings reveal androgen-induced ferroptosis as a key mechanism in placental dysfunction and highlight a potential application of metformin for treatment of early pregnancy loss associated with PCOS.