In 2015, Tu Youyou's team won the Nobel Prize in Physiology or Medicine for isolating artemisinin from traditional Chinese medicine and applying it to the treatment of malaria. In 2021, the World Health Organization announced that China had passed the malaria elimination certification, making China the first country in the WHO Western Pacific Region to be certified as malaria-free in more than 30 years. Artemisinin, known as the "Chinese magic herb", saves countless malaria patients around the world every year. Three years later, a team from Fudan University published a paper in Science magazine, revealing the potential of artemisinin in treating polycystic ovary syndrome. Written by | Luffy On June 13, 2024, a team from the School of Basic Medicine of Fudan University and a team from Zhongshan Hospital Affiliated to Fudan University jointly published the latest research results on artemisinin online in the journal Science - "Artemisinins ameliorate polycystic ovarian syndrome by mediating LONP1-CYP11A1 interaction". The research team found that artemisinin derivatives can significantly improve the disease phenotype of polycystic ovary syndrome. Paper publication page Standing on the shoulders of giants Polycystic ovary syndrome (PCOS) is one of the most common reproductive endocrine disorders and the main culprit of infertility in women of childbearing age, with a global incidence of approximately 10%-13%. According to the diagnostic criteria published in Rotterdam in 2003, PCOS can be diagnosed if two of the following three characteristics are met: one is anovulation or occasional ovulation, that is, no menstruation or menstrual cycle disorder; the second is hyperandrogenemia or clinical manifestations of hyperandrogenism; the third is polycystic ovary changes. Among them, elevated androgen is one of the most typical symptoms, and it is also the direct cause of impaired follicular development and abnormal ovulation in patients. Reducing the androgen level of PCOS patients is currently the main way to treat PCOS. In addition, PCOS patients are often accompanied by obesity, insulin resistance and abnormal diabetes metabolism. As the disease progresses, it can also cause cardiovascular and cerebrovascular diseases, reproductive system tumors, and mental disorders, posing a serious threat to women's reproductive fertility and life health. However, the academic community has not yet figured out the pathogenesis of PCOS. Clinically, only symptomatic treatment is available, with combined oral contraceptives often used to reduce hyperandrogenism, but this does not improve infertility or the morphology of polycystic ovaries. In short, the treatment effect is not ideal. Artemisinin is a sesquiterpene lactone compound derived from Artemisia annua. It has been used as a first-line antimalarial drug in clinical practice due to its stable efficacy and few side effects. Malaria is a vector-borne infectious disease caused by infection with Plasmodium through the bite of Anopheles mosquitoes, while PCOS is a reproductive endocrine disorder with an unknown cause. At first glance, malaria and PCOS are not related at all. How did the researchers use their imagination to link artemisinin with PCOS? "This is mainly due to standing on the shoulders of giants," said Liu Yang, associate professor at the School of Basic Medical Sciences of Fudan University, the first author of the study. The idea of starting this research emerged in 2016, when he was a postdoctoral student at Fudan University and affiliated with the Obstetrics and Gynecology Hospital of Fudan University, studying the development and metabolic regulation of fat cells. Liu Yang's original intention was to find a connection between his personal research field and common female reproductive diseases in clinical practice, and then solve clinical problems. Liu Yang's doctoral supervisor, Professor Tang Qiqun, has been deeply engaged in the research of fat cells. The academic community divides adipose tissue into three types. White fat is responsible for storing energy, while brown and beige fat can convert the energy generated by the metabolism of nutrients into heat energy to maintain body temperature. The classic brown fat in the human body only appears in infancy, while beige fat is mainly distributed in adults. The activation of brown fat and the beigeization of white fat can promote the body's energy consumption and have always been regarded as an effective strategy to fight obesity. Therefore, how to activate the beigeization of white fat and improve metabolism has become a cutting-edge issue in the field. In 2015, Professor Tu Youyou won the Nobel Prize in Physiology or Medicine, and artemisinin became a hot topic in academic research. In 2016, Professor Tang Qiqun's team published a paper in Cell Research, which systematically screened small molecule compounds that promote beige white fat and found that artemisinin derivatives, artemisinin methyl ether (ATM), can promote beige white fat and enhance the function of brown fat, playing a good role in preventing and treating obesity-induced metabolic syndrome. In the same year, the PNAS journal published an important study on the ability of brown fat transplantation to treat polycystic ovary syndrome. It was found that after transplanting exogenous brown adipose tissue (BAT) into PCOS model rats, endogenous BAT was significantly activated, insulin resistance was significantly improved, regular ovulation was restored, and the pregnancy rate was improved. It should be added that previous studies have shown that PCOS patients have abnormal brown fat function, which leads to metabolic disorders such as insulin resistance. In other words, brown adipose tissue plays a vital role in the treatment of PCOS. These two articles gave the research team a direction: Can artemisinin affect the occurrence and development of PCOS? Unraveling the mystery and pursuing victory Molecular mechanism of artemisinin derivatives in inhibiting PCOS In order to study whether artemisinin has a therapeutic effect on PCOS, the research team used exogenous androgen, dehydroepiandrosterone (DHEA), to construct PCOS-like mouse and rat models. At the same time, the team also used insulin and human chorionic gonadotropin hCG to construct another PCOS-like rat model, and used the artemisinin derivative artemether (ATM) to treat the above models. The experimental results made the research team very excited. Whether injected intraperitoneally or orally, ATM can significantly inhibit serum androgen levels, improve the estrus cycle of PCOS-like animal models, reduce the number of cystic follicles in the ovaries, and improve the fertility of PCOS-like rats. So, how does artemether reduce androgen levels? The team conducted further research with these questions. The hypothalamus-pituitary-ovarian axis plays an important neuroendocrine role in steroid hormone production. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are upstream hormones that control steroid hormone synthesis. Taking this as a starting point, the research team explored whether ATM is directly involved in controlling upstream hormones that control androgen synthesis. However, in the PCOS-like model, ATM had no effect on FSH and LH, whether administered intraperitoneally or orally, indicating that ATM does not regulate androgens by changing the production of gonadotropins. The team further hypothesized that ATM may regulate testosterone levels directly by targeting the ovaries. To verify this idea, the research team measured steroid hormones in the supernatant of ovarian theca-stromal cells. The experiment showed that artemisinin derivatives inhibited the steroidogenesis process and subsequent androgen synthesis of ovarian theca-stromal cells. To further explore the cellular pathways by which artemisinin derivatives induce reduced androgen synthesis, the team performed mass spectrometry-based relative quantitative proteomics analysis on theca-stromal cells isolated before and after ATM treatment, and found that CYP11A1 was the most significantly downregulated protein induced by ATM. CYP11A1 can catalyze the conversion of cholesterol to pregnenolone and is the rate-limiting enzyme for androgen synthesis. To verify the proteomics data, the research team detected the expression of steroid hormone synthases in theca-stromal cells of mice and rats, and found that artemisinin derivatives could dose-dependently downregulate CYP11A1 protein. In cells lacking CYP11A1, artemisinin derivatives could not further inhibit androgen synthesis, indicating that they inhibited androgen synthesis by downregulating CYP11A1 protein. What is the regulatory mechanism of artemisinin derivatives on CYP11A1? The research team used immunoprecipitation combined with mass spectrometry (IP-MS) to identify the interacting proteins of CYP11A1 under ATM treatment. Based on the IP-MS data, it was found that artemisinin derivatives can promote the interaction between LONP1 and CYP11A1 protein. LONP1 is an AAA+ mitochondrial protease that degrades misfolded or oxidized proteins by utilizing ATP hydrolysis, and is crucial in protein quality control in mitochondria. The research team found that LONP1 can respond to artemisinin derivatives and degrade CYP11A1, thereby inhibiting the synthesis of ovarian androgens. Promoting large-scale clinical trials Experiments on rodents revealed that artemisinin derivatives have the efficacy of treating PCOS symptoms. The research team then recruited 19 PCOS patients for clinical research. The patients took dihydroartemisinin (40 mg, 3 times a day) orally for 12 weeks. Before the experiment, all patients had hyperandrogenemia, oligomenorrhea or amenorrhea, and polycystic ovary symptoms. After the experiment, no side effects were observed in all participants. Dihydroartemisinin treatment significantly reduced serum testosterone levels in PCOS patients. Anti-Müllerian hormone (AMH) is mainly produced by granulosa cells of preantral follicles and small antral follicles in the ovaries. AMH is usually higher in PCOS patients, and dihydroartemisinin treatment significantly reduced serum AMH. In addition, 12 PCOS patients resumed regular menstrual cycles after treatment. In summary, dihydroartemisinin effectively improved hyperandrogenemia, improved the morphology of polycystic ovaries, and contributed to the normalization of menstruation in PCOS patients. At the same time, Science published a special review titled "Remedy hope for polycystic ovary syndrome" by Professor Elisabet Stener-Victorin of the Karolinska Institute in Sweden, who believed that the study provided new hope for the treatment of PCOS. "Although the use of exogenous androgens to create models is a common practice in the industry, these models cannot fully replicate the complex situation of female PCOS. This study used the peripubertal DHEA model, which can make PCOS-like mice show elevated serum testosterone levels, irregular estrous cycles and polycystic ovary morphology. However, this model also exhibits other endocrine diseases including hyperprolactinemia, so it cannot fully reflect the characteristics of female PCOS." Although the team's article was published in a top journal, Liu Yang is still "concerned" about the limitations of the research. Developing an animal model that better reflects the onset of human PCOS is also an urgent problem to be solved in the field. "The team is currently further optimizing the dosage and duration of dihydroartemisinin, and plans to conduct larger-scale clinical studies in the future," Liu Yang said. "In addition to improving the clinical symptoms of women with PCOS, the team will also pay more attention to the fertility of PCOS patients in the future, in order to provide solutions to solve fertility problems for women of childbearing age." Special Tips 1. Go to the "Featured Column" at the bottom of the menu of the "Fanpu" WeChat public account to read a series of popular science articles on different topics. 2. Fanpu provides a function to search articles by month. Follow the official account and reply with the four-digit year + month, such as "1903", to get the article index for March 2019, and so on. Copyright statement: Personal forwarding is welcome. 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