Endometriosis (EMs) is a life-long endocrine disorder and a common cause for female infertility and pelvic pain. The key characteristics of eutopic endometrium of EMs patients are high proliferative and migratory potentials. Cuproptosis is a recently identified copper- and-mitochondrial-dependent regulated cell death. Regretfully, its role in EMs remains unclear. In this study, Kyoto Encyclopedia of Genes and Genomes analyses of differentially expressed genes (DEGs) indicated strong activation of the PI3K-Akt-mTOR pathway and biological process analysis reported positive regulation of kinase activity. Next, we screened 11 cuproptosis-related DEGs and found all of them were downregulated in the EMs group, which indicated the suppression of cuproptosis in EMs. One key cuproptosis-related gene, PDHA1, was selected via support vector machine, random forest algorithm and lasso regularization to build a risk-scoring model, which was tested in both internal and external validations. In conclusion, the downregulation and kinase activity of PDHA1 may function with the PI3K-Akt-mTOR pathway in some way, which could suppress the cuproptosis level and account for the cancer-like pathology in EMs.

Radiological therapy/examination is the primary source of artificial radiation exposure in humans. While its application has contributed to major advances in disease diagnosis and treatment, ionizing radiation exposure is associated with ovarian damage. The use of natural products, either alone or as an adjunct, has become increasingly common for reducing the side effects of radiological therapy during disease treatment. Herein, we explored the protective effect of folic acid (FA), a widely used B vitamin, against radiation-induced ovarian injury and its mechanism of action. Female mice with normal ovarian function were randomly divided into control, FA, radiation, and radiation + FA groups. The intervention strategy included daily intragastric administration of FA (5 mg/kg) for 3 weeks prior to radiation exposure. Mice in the radiation and radiation + FA groups received a single dose of 5 Gy X-ray irradiation. Changes in the estrous cycle were then recorded, and ovarian tissues were collected. Pathophysiological changes as well as reproductive and endocrine-related indexes were determined via H&E staining, immunohistochemistry, Western blot, and ELISA. The reproductive performance and emotional symptoms of animals were also monitored. Our results indicated that FA intervention effectively alleviated ovarian damage, leading to more regular estrous cycles, lesser impairment of follicular morphology and endocrine status, as well as greater germ cell preservation. Reduced levels of oxidative stress, inflammation, and enhanced DNA repair were associated these changes. FA pre-administration improved the reproductive performance, leading to higher pregnancy rates and greater litter sizes. Further, the anxiety levels of animals were significantly reduced. Our results indicate that FA pre-administration significantly alleviates radiation-induced ovarian damage in rodents, highlighting its potential as a protective strategy against radiation exposure in the female population.

The GNAS locus is an imprinted site. The α‐subunit of the stimulatory G protein (Gsα) and extralarge variant (XLαs) are the two important products of the GNAS locus. The abnormal expression of Gsα is associated with pseudohypoparathyroidism (PHP) and related disorders, including Albright hereditary osteodystrophy (AHO), pseudopseudohypoparathyroidism (PPHP), and progressive osseous heteroplasia (POH). XLαs protein can mimic the catalytic intracellular synthesis of cyclic adenosine monophosphate (cAMP) by Gsα in response to parathyroid hormone (PTH) stimulation, which may be involved in the pathogenesis of PPHP and POH in patients with paternal GNAS defects. A paternally inherited nonsense variant in the first exon of XLαs in an adult patient may be associated with fractures and osteopetrosis. The relationship between the XLαs product of the GNAS locus and bone remodeling may have been overlooked. Here, we summarize the phenotypes of genetic mouse models and clinical cases of XLαs variations and suggest that the abnormal paternal expression of XLαs may be associated with the development of POH and affect osteoblast and osteoclast differentiation.