Asialoglycoprotein receptor-1 promotes hyperandrogenism in polycystic ovary syndrome through direct interaction with FSHR, leading to cAMP-PKA-CREB pathway inhibition.

In brief: Asialoglycoprotein receptor 1 (ASGR1) impairs FSH receptor trafficking and reduces the cAMP-PKA-CREB signaling pathway, thereby suppressing the expression of the target gene CYP19A1. This impairs the conversion of testosterone to estradiol, ultimately contributing to the development of hyperandrogenemia in polycystic ovary syndrome. Abstract: Polycystic ovary syndrome (PCOS) is a prevalent multifactorial disorder characterized by hormone dysregulation and follicular development defects. Asialoglycoprotein receptor 1 (ASGR1), a C-type lectin predominantly expressed on the hepatic cell membrane, functions as a glycoprotein receptor that primarily mediates the binding, endocytosis and subsequent degradation of specific ligands. Notably, this receptor recognizes glycan moieties commonly carried by plasma glycoproteins-including glycoprotein hormones-and is thereby implicated in cellular signal transduction and material metabolism. In this study, we explored the potential association between ASGR1 and PCOS, and systematically explored its functional role and underlying mechanisms in PCOS pathogenesis. In-vivo experiments showed that ovarian-specific overexpression of Asgr1 (adeno-associated virus [AAV]-Asgr1 mice) resulted in typical PCOS-like phenotypes. Mechanistically, we found that Asgr1 overexpression directly inhibited the activation of the cAMP-PKA-CREB signaling pathway-a key pathway mediating FSH-regulated ovarian functions. Further in-vitro and in-vivo experiments revealed that ASGR1 exerted this effect at least in part by mediating the endocytosis and lysosomal degradation of FSH, thereby reducing subsequent downstream signaling activation. Conversely, the ovarian-specific knockdown of Asgr1 (AAV-sh-Asgr1 mice) showed a significant improvement in PCOS-related abnormalities.