Transcription repression of estrogen receptor alpha by ghrelin/Gq/11/YAP signaling in granulosa cells promotes polycystic ovary syndrome.

Polycystic ovarian syndrome (PCOS) is a prevalent endocrinological disorder affected by ghrelin. This study aimed to investigate the molecular mechanisms underlying the effects of ghrelin on PCOS manifestations in mice and to assess the therapeutic potential of ghrelin. Female C57BL/6 mice were subcutaneously injected with 6 mg/100 g dehydroepiandrosterone (DHEA) for 20 days to induce PCOS. Alterations in reproductive cycles, ovarian morphology, serum sex hormone levels, and related signaling markers were examined. Furthermore, ghrelin-induced effects on granulosa cells and the role of ghrelin/Gq/11/ Yes-associated protein (YAP) signaling were studied by silencing Gαq/11 or YAP using si-RNAs. Finally, we evaluated the therapeutic potential of anti-ghrelin antibodies in DHEA-induced PCOS mice. DHEA administration led to significant PCOS-associated changes including weight gain, disrupted estrous cycles, ovarian morphological alterations, and hormonal imbalances in mice, with elevated Gαq/11 and acylated ghrelin expression, which was also noted in PCOS patients. However, treatment with anti-ghrelin antibodies effectively managed DHEA-induced damage in PCOS mice. In vitro, ghrelin exposure resulted in granulosa cell injury and modulated estrogen receptors alpha (ERα) and YAP protein levels, whereas silencing YAP and Gαq/11 reversed ghrelin-induced detrimental effects and up-regulated ERα expression. This study revealed that DHEA-induced PCOS traits in mice could be improved by anti-ghrelin antibodies, with the ghrelin/Gq/11/YAP signaling pathway identified as a crucial mediator in granulosa cells, affecting ERα transcription to regulate PCOS. These findings suggest a potential therapeutic strategy for the treatment of PCOS.

Zhu P ，Bi X ，Su D ，Li X ，Chen Y ，Song Z ，Zhao L ，Wang Y ，Xu S ，Wu X ... -  《Human Cell》

Ghrelin Alleviates Inflammation, Insulin Resistance, and Reproductive Abnormalities in Mice with Polycystic Ovary Syndrome via the TLR4-NF-κB Signaling Pathway.

Liu F ，Wang X ，Zhao M ，Zhang K ，Li C ，Lin H ，Xu L ... -  《-》

PPAR-α inhibits DHEA-induced ferroptosis in granulosa cells through upregulation of FADS2.

Polycystic ovary syndrome (PCOS), a prevalent endocrine disorder among women of reproductive age, is characterized by disturbances in hormone levels and ovarian dysfunction. Ferroptosis, a unique form of regulated cell death characterized by iron-dependent lipid peroxidation. Emerging evidence indicates that ferroptosis may have a significant role in the pathogenesis of PCOS, highlighting the importance of studying this mechanism to better understand the disorder and potentially develop novel therapeutic interventions. To create an in vivo PCOS model, mice were injected with dehydroepiandrosterone (DHEA) and the success of the model was confirmed through further assessments. Ferroptosis levels were evaluated through detecting ferroptosis-related indicators. Ferroptosis-related genes were found through bioinformatic analysis and identified by experiments. An in vitro PCOS model was also established using DHEA treated KGN cells. The molecular binding relationship was confirmed using a chromatin immunoprecipitation (ChIP) assay. In PCOS model, various ferroptosis-related indicators such as MDA, Fe2+, and lipid ROS showed an increase, while GSH, GPX4, and TFR1 exhibited a decrease. These findings indicate an elevated level of ferroptosis in the PCOS model. The ferroptosis-related gene FADS2 was identified and validated. FADS2 and PPAR-α were shown to be highly expressed in ovarian tissue and primary granulosa cells (GCs) of PCOS mice. Furthermore, the overexpression of both FADS2 and PPAR-α in KGN cells effectively suppressed the DHEA-induced increase in ferroptosis-related indicators (MDA, Fe2+, and lipid ROS) and the decrease in GSH, GPX4, and TFR1 levels. The ferroptosis agonist erastin reversed the suppressive effect, suggesting the involvement of ferroptosis in this process. Additionally, the FADS2 inhibitor SC26196 was found to inhibit the effect of PPAR-α on ferroptosis. Moreover, the binding of PPAR-α to the FADS2 promoter region was predicted and confirmed. This indicates the regulatory relationship between PPAR-α and FADS2 in the context of ferroptosis. Our study indicates that PPAR-α may have an inhibitory effect on DHEA-induced ferroptosis in GCs by enhancing the expression of FADS2. This discovery provides valuable insights into the pathophysiology and potential therapeutic targets for PCOS.

Liu Y ，Ni F ，Huang J ，Hu Y ，Wang J ，Wang X ，Du X ，Jiang H ... -  《-》

Modulation of steroidogenesis by vitamin D3 in granulosa cells of the mouse model of polycystic ovarian syndrome.

Bakhshalizadeh S ，Amidi F ，Alleyassin A ，Soleimani M ，Shirazi R ，Shabani Nashtaei M ... -  《-》

Silencing of LncRNA steroid receptor RNA activator attenuates polycystic ovary syndrome in mice.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and has a prevalence of 1 in 15 women worldwide. This study aims to investigate the role of lncRNA SRA in the pathological processes of polycystic ovary syndrome (PCOS). Twenty five-day old female C57BL/6 mice received subcutaneous injection of 60 mg/kg dehydroepiandrosterone for 20 days to induce PCOS. Lentivirus containing lncRNA SRA-specific shRNA was subcapsularly injected into the ovaries of PCOS mice. Granulosa cell was primary cultured to explore the mechanism of DHEA-induced inflammatory responses. H&E staining was used to examine the histological changes of ovaries. ELISA was used to assess serum insulin level and proinflammatory cytokines and angiogenetic factors contents in ovary tissue. The expression levels of LncRNA SRA and proteins involved in the NF-κB signaling pathway were detected through Quantitative real-time PCR and Western blot. The nuclear translocation of NF-κB was observed by immunofluorescence and the activity of NF-κB-DNA binding was detected using EMSA. Silencing of lncRNA SRA changed insulin release, attenuated ovary injury and reduced the production of angiogenetic factors in the PCOS mice. In addition, shRNA targeting lncRNA SRA inhibited DHEA-induced pro-inflammatory cytokines production and NF-κB nuclear translocation in the ovary of PCOS mice and primary granulosa cells. Silencing of lncRNA Steroid Receptor RNA Activator (SRA) attenuates polycystic ovary syndrome (PCOS) in mice. LncRNA SRA plays important roles in the development of PCOS.

Li Y ，Zhao W ，Wang H ，Chen C ，Zhou D ，Li S ，Zhang X ，Zhao H ，Zhou D ，Chen B ... -  《-》