Endometriosis (EMs) occurs in approximately 50% of women with infertility. The main causes of EMs-related infertility are follicle dysplasia and reduced oocyte quality. Iron overload occurs in ovarian follicular fluid (FF) of patients with EMs, and this condition is associated with oocyte maturation disorder. However, the underlying molecular mechanism remains largely unknown. In the present study, we identified the mechanism underlying ferroptosis in ovarian granulosa cells and oocyte maturation failure in EMs based on a retrospective review of in vitro fertilization/intracytoplasmic sperm injection-frozen embryo transfer outcomes in infertile patients with EMs. Mouse granulosa cells were treated with EMs-related infertile patients' follicular fluid (EMFF) in vitro. Western blot analysis, quantitative polymerase chain reaction, fluorescence staining, and transmission electron microscopy were used to assess granulosa cells ferroptosis. The effects of exosomes were examined by nanoparticle tracking analysis, RNA-seq, and Western blot analysis. Finally, the therapeutic values of vitamin E and iron chelator (deferoxamine mesylate) in vivo were evaluated in an EMs-related infertility model. Patients with ovarian EMs experienced poorer oocyte fertility than patients with non-ovarian EMs. We observed that EMFF with iron overload-induced granulosa cell ferroptosis in vitro and in vivo. Mechanically, nuclear receptor coactivator four-dependent ferritinophagy was involved in this process. Notably, granulosa cells undergoing ferroptosis further suppressed oocyte maturation by releasing exosomes from granulosa cells. In therapeutic studies, vitamin E and iron chelators effectively alleviated EMs-related infertility models. Our study indicates a novel mechanism through which EMFF with iron overload induces ferroptosis of granulosa cells and oocyte dysmaturity in EMs-related infertility, providing a potential therapeutic strategy for EMs-related infertility.

ObjectivesTo determine the therapeutic effect of a Mediterranean diet (MED) combined with a low-carbohydrate (LC) dietary model in overweight polycystic ovary syndrome (PCOS) patients.MethodsIn this 12-week randomized controlled clinical trial, 72 overweight patients with PCOS were randomly assigned to one of two energy-restricted dietary models: the MED/LC diet or the Low fat (LF) diet. After the intervention, the number of the two groups returned to normal menstruation was counted. Body weight, body mass index (BMI), waist circumference, waist-hip ratio (WHR), body fat percentage (BF%), serum fasting insulin(FINS), fasting plasma glucose(FPG), insulin resistance index (HOMA-IR), quantitative insulin sensitivity index (QUIKI), total cholesterol (TC) and high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglyceride (TG), total testosterone (TT), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin (PRL) were compared between 2 groups before and after intervention.ResultsMED/LC group had more significant reduction trend in weight (−6.10 ± 1.52 kg vs −4.79 ± 0.97 kg, P < 0.05), BMI (−2.12 ± 0.57 kg/m2 vs −1.78 ± 0.36 kg/m2, P < 0.05), WC (−6.12 ± 5.95 cm vs −3.90 ± 1.58 cm, P < 0.05), WHR (−0.06 ± 0.02 vs −0.03 ± 0.02, P < 0.05), BF% (−2.97% ± 1.78% vs −1.19% ± 0.91%, P < 0.05), TT (−0.20 ± 0.24 ng/mL vs 0.08 ± 0.11 ng/Ml, P < 0.001), LH (−5.28 ± 3.31 mIU/mL vs −3.39 ± 3.64 mIU/mL, P < 0.05), and LH/FSH (−1.18 ± 0.75 vs -0.66 ± 1.05, P < 0.05) compared with the LF group. In addition, FPG (0.05 ± 0.38 mmol/mL vs -0.50 ± 1.01 mmol/mL, P < 0.001), FINS (−4.88 ± 6.11 μU/mL vs −8.53 ± 5.61 μU/mL, P < 0.01), HOMA-IR index (−1.11 ± 1.51 vs −2.23 ± 0.25, P < 0.05), and QUIKI index (0.014 ± 0.016 vs 0.028 ± 0.019, P < 0.05) decreased significantly in the MED/LC group compared with the LF group. Comparing the changes in lipid parameters between the two groups (LF vs MED/LC), significant differences in TG (−0.33 ± 0.32 mmol vs −0.76 ± 0.97 mmol, P < 0.05), TC (−0.40 ± 1.00 mmol vs −1.45 ± 2.00 mmol, P < 0.05), and LDL-C (−0.41 ± 1.05 mmol vs −0.73 ± 0.76 mmol, P < 0.05) were observed.ConclusionThe results of this study suggest that the MED/LC diet model is a good treatment for overweight PCOS patients, significantly restoring their menstrual cycle, improving their anthropometric parameters and correcting their disturbed endocrine levels, and its overall effectiveness is significantly better than the LF diet model. Therefore, this study recommends that the MED/LC diet model can be used in the clinical treatment of patients with overweight PCOS.

Objective. Bushen Huoxue Huatan Decoction (BHHD) is a classic prescription for treating polycystic ovary syndrome (PCOS). This study aims to explore the effects and possible mechanisms of BHHD on PCOS by integrating network pharmacology and clinical study. Methods. The components and potential drug targets of BHHD were analysed using the TCMSP platform, and the potential pathogenesis targets for PCOS were analysed using the GeneCards and OMIM databases. Subsequently, a disease-compound-target network diagram was established to identify the targets of BHHD treatment on PCOS. In addition, protein-protein interaction analysis, KEGG pathway analysis, and Gene Ontology biological analysis were carried out to reveal the mechanisms of BHHD. To further validate the analysis, a clinical trial involving 62 PCOS patients was conducted. All patients were treated with BHHD for 3 months and the ovulation rate, anthropometric indicators, clinical symptoms, and serological indicators were measured and compared before and after treatment. Results. The network pharmacology analysis showed that quercetin, luteolin, and kaempferol are the most significant active components in BHHD; STAT3, Jun, AKT1, MAPK3, MAPK1, and TP53 are the most critical drug targets; regulating hormones, reversing insulin (INS) resistance, exerting anti-inflammatory effects, and improving fertility might be the most important mechanisms of BHHD in the treatment of PCOS. After BHHD administration, the cyclic ovulation rate and the clinical symptoms including acanthosis nigricans and acne of patients were obviously improved. The serum endocrine levels of luteinising hormone (LH), LH/follicle-stimulating hormone, testosterone, dehydroepiandrosterone sulphate, insulin (INS), and area under the INS curve were evidently reversed, and the serum inflammatory factors levels including human interleukin (IL)-18, IL-16, IL-1β, IL-8, macrophage migration inhibitory factor, and human leukocyte differentiation antigen CD40 ligand were greatly reduced. Conclusion. BHHD has a good therapeutic effect on PCOS, and its mechanisms may be related to regulating hormone levels, improving insulin resistance, alleviating inflammation, and promoting pregnancy.

Ovarian cancer (OC) is a highly malignant gynecologic tumor with few treatments available and poor prognosis with the currently available diagnostic markers and interventions. More effective methods for diagnosis and treatment are urgently needed. Although the current evidence implicates ferroptosis in the development and therapeutic responses of various types of tumors, it is unclear to what extent ferroptosis affects OC. To explore the potential of ferroptosis-related genes as biomarkers and molecular targets for OC diagnosis and intervention, this study collected several datasets from The Cancer Genome Atlas-OC (TCGA-OC), analyzed and identified the coexpression profiles of 60 ferroptosis-related genes and two subtypes of OC with respect to ferroptosis and further examined and analyzed the differentially expressed genes between the two subtypes. The results indicated that the expression levels of ferroptosis genes were significantly correlated with prognosis in patients with OC. Single-factor Cox and LASSO analysis identified eight lncRNAs from the screened ferroptosis-related genes, including lncRNAs RP11-443B7.3, RP5-1028K7.2, TRAM2-AS1, AC073283.4, RP11-486G15.2, RP11-95H3.1, RP11-958F21.1, and AC006129.1. A risk scoring model was constructed from the ferroptosis-related lncRNAs and showed good performance in the evaluation of OC patient prognosis. The high- and low-risk groups based on tumor scores presented obvious differences in clinical characteristics, tumor mutation burden, and tumor immune cell infiltration, indicating that the risk score has a good ability to predict the benefit of immunotherapy and may provide data to support the implementation of precise immunotherapy for OC. Although in vivo tests and research are needed in the future, our bioinformatics analysis powerfully supported the effectiveness of the risk signature of ferroptosis-related lncRNAs for prognosis prediction in OC. The findings suggest that these eight identified lncRNAs have great potential for development as diagnostic markers and intervention targets for OC and that patients with high ferroptosis-related lncRNA expression will receive greater benefits from conventional chemotherapy or treatment with ferroptosis inducers.