PPT1 regulation of HSP90a depalmitoylation participates in the pathogenesis of hyperandrogenism

Ovarian granulosa cells (GCs) in the follicle are the important mediator of steroido-genesis and foster oocyte maturation. Evidences suggested that the function of GCs could be regulated by S-palmitoylation. However, the role of S-palmitoylation of GCs in ovarian hyperandrogenism remains elusive. Here, we demonstrated that the protein from GCs in ovarian hyperandrogenism phenotype mouse group ex-hibits lower palmitoylation level compared with that in the control group. Using S-palmitoylation-enriched quantitative proteomics, we identified heat shock pro-tein isoform a (HSP90a) with lower S-palmitoylation levels in ovarian hyperandro-genism phenotype group. Mechanistically, S-palmitoylation of HSP90a modulates the conversion of androgen to estrogens via the androgen receptor (AR) signalling pathway, and its level is regulated by PPT1. Targeting AR signaling by using dipyr-idamole attenuated ovarian hyperandrogenism symptoms. Our data help eluci-date ovarian hyperandrogenism from perspective of protein modification and provide new evidence showing that HSP90a S-palmitoylation modification might be a potential pharmacological target for ovarian hyperandrogenism treatment.