Cervical squamous cell carcinoma (CSCC) is a type of female cancer that affects millions of families worldwide. Human papillomavirus (HPV) infection is the main reason for CSCC formation, and squamous intraepithelial lesions (SILs) induced by high-risk HPV (HR-HPV) infection are considered precancerous lesions. A previous study reported that HPV-infected cancer cells were able to counteract lipid peroxidation for survival. Recent research has reported that ferroptosis acts in an iron-dependent lipid peroxidation manner to kill cancer cells, and it is proposed as a new approach for female cancer therapy. Here, we investigated the role of ferroptosis throughout SIL development into CSCC. We found that ferroptosis occurred in SIL, but anti-ferroptosis emerged in CSCC. Our data further indicated that an antiferroptotic effect was formed in response to persistent ferroptosis and then promoted oncogenesis. Altogether, we provide novel insight into ferroptosis in cervical SIL development and suggest a potential therapeutic target for the treatment of CSCC.

Background: Male infertility has become a worldwide public health problem. However, the effect of low body mass index (BMI) is still controversial. Methods: Relevant articles in Pubmed, Embase, Web of science, and Wanfang database published until September 2017 were searched without language restriction. We performed a meta-analysis about low BMI and semen parameters containing total sperm count, concentration, semen volume, and sperm motility (overall and progressive), including 709 men with low BMI and 14,622 men with normal BMI. Results: Thirteen studies were included in this meta-analysis and a total of 15,331 individuals were accumulated. We pooled data from these articles and found standardized weighted mean differences in semen parameters (total sperm count and semen volume) showed significant difference between low BMI and normal BMI. Conclusions: This systematic review with meta-analysis has confirmed that there was a relationship between low BMI and semen quality, which suggesting low BMI may be a harmful factor of male infertility. Yet lacking of the raw data may influence the accuracy of the results. Further researches are needed to identify the role of underweight in male sterility.

Squamous intraepithelial lesion of cervix (SIL) in human papillomavirus (HPV)-positive patient often undergoes a silent and long-course development, and most of them with high-grade transit to cervical squamous cell carcinoma (CSCC). The oxysterol 25-hydroxycholesterol (25-HC) is associated with HPV inhibition, autophagy and cholesterol synthesis, however, its function in this long process of SIL development remain unclear. In this study, we demonstrate that 25-HC generation is inhibited through HSIL-to-CSCC transition. The 25-HC activates ferritinophagy in the early stage of SIL, promoting the vulnerability of HSILs to ferroptosis. Therefore, maintaining 25-HC level is crucial for suppressing HSIL progression and holds promise for developing novel clinical therapies for CSCC.

Cuproptosis is a newly defined regulated cell death model and is considered as a potential approach for cancer treatment. We have previously found that cervical cancer cells have the capability of anti-ferroptosis. A recent study has reported that elesclomol (ES) is able to induce copper-dependent ferroptosis. However, its effect on cervical cancer cell ferroptosis is still unclear. In this study, we found that the expression levels of copper metabolism-related genes ATP7A and ATP7B were decreased in cervical cancer tissues. In cervical cancer cells, combined treatment of ES and Cu²⁺ inhibited cell proliferation and promoted cell death, but did not promote cuproptosis. However, ES-Cu²⁺ treatment led to the accumulation of cellular reactive oxygen species, increased cellular Fe²⁺ levels, and decreased expression of GPX4. Moreover, the expression levels of HMOX1 and FTH1 were increased, while the expression level of TFRC was decreased after co-treated with ES-Cu²⁺ in cervical cancer cells. The decreased expression of GPX4 induced by ES-Cu²⁺ was attenuated by ferroptosis inhibitors ferrostatin-1 and DFO. Knockdown of HMOX1 could alleviate ES-Cu²⁺-induced GPX4 downregulation. The expression level of HMOX1 was upregulated in cervical cancer tissues and was negatively associated with ATP7B. In conclusion, copper metabolism is altered in cervical cancer tissues. ES-Cu²⁺ co-treatment induce ferroptosis in cervical cancer cells by upregulating HMOX1. Our study provides new insights into the relation between cuproptosis and ferroptosis, which may be potential for clinical therapies of cervical cancer.

Prenatal androgen exposure induces metabolic disorders in female offspring. However, the long-term effect of maternal testosterone excess on glucose metabolism, especially on pancreatic beta cell function, is rarely investigated. Our current study mainly focused on the effects of prenatal testosterone exposure on glucose metabolism and pancreatic beta cell function in aged female offspring. By using maternal mice and their female offspring as animal models, we found that prenatal androgen treatment induced obesity and glucose intolerance in aged offspring. These influences were accompanied by decreased fasting serum insulin concentration, elevated serum triglyceride and testosterone concentrations. Glucose stimulated insulin secretion in pancreatic beta cells of aged female offspring was also affected by prenatal testosterone exposure. We further confirmed that increased serum testosterone contributed to down regulation of Sirtuin 3 expression, activated oxidative stress and impaired pancreatic beta cell function in aged female offspring. Moreover, over-expression of Sirtuin 3 in islets isolated from female offspring treated with prenatal testosterone normalized the oxidative stress level, restored cyclic adenosine monophosphate and adenosine triphosphate generation, which finally improved glucose stimulated insulin secretion in beta cells. Taken together, these results demonstrated that prenatal testosterone exposure caused metabolic disturbance in aged female offspring via suppression of Sirtuin 3 expression and activation of oxidative stress in pancreatic beta cells.