In:
Science, American Association for the Advancement of Science (AAAS), Vol. 384, No. 6701 ( 2024-06-14)
Abstract:
Polycystic ovarian syndrome (PCOS), a prevalent reproductive endocrine disorder affecting 10 to 13% of women in their reproductive age, is characterized by hyperandrogenemia, ovulatory dysfunction, polycystic ovarian morphology, and often by associated metabolic disorders. Androgen excess is a key factor driving the phenotypic features of PCOS. Despite the high prevalence of PCOS, pharmacologic interventions for such a complicated syndrome encounter substantial challenges. The treatment options currently available for PCOS are limited and mainly tailored to management of specific symptoms. Consequently, there is a compelling and urgent need for the development of innovative therapeutic strategies. RATIONALE Artemisinin, derived from Artemisia plants, is widely recognized for its efficacy against malaria. We have previously demonstrated that artemisinin and its derivatives possess the capability to enhance energy expenditure and insulin sensitivity through the activation of thermogenic adipocytes, thereby protecting against diet-induced obesity and metabolic disorders. In this study, we explored the therapeutic potential of artemisinins in rodent PCOS-like models and human patients with PCOS by evaluating the effect of artemisinin derivatives on testosterone level, estrous cycle, and polycystic ovarian morphology. Using in vitro and in vivo approaches, we investigated the impact of artemisinins on ovarian testosterone synthesis. The direct target of artemisinins was identified to elucidate the mechanism governing the regulation of testosterone synthesis by artemisinins. RESULTS We found that artemisinin analog artemether exhibited considerable improvements in hyperandrogenemia, irregular estrous cycles, polycystic ovarian morphology, and low fertility in the PCOS-like rodent models. Artemisinins inhibited hyperandrogenemia by repressing ovarian testosterone synthesis. Relative quantitative proteomics analysis revealed cytochrome P450 family 11 subfamily A member 1 (CYP11A1), the enzyme catalyzing the initial step of androgen synthesis, as the most notably decreased protein affected by artemisinins. Further investigation showed that artemisinins induced the degradation of CYP11A1, leading to the inhibition of ovarian androgen synthesis. This inhibitory effect was diminished in the absence of CYP11A1. Mechanistically, artemisinins directly targeted the lon peptidase 1 (LONP1), enhancing the interaction between LONP1 and CYP11A1 and promoting the LONP1-catalyzed degradation of CYP11A1. Conversely, androgenic inducer disrupted the binding between LONP1 and CYP11A1; additionally, LONP1 was down-regulated in PCOS, resulting in elevated CYP11A1 levels and increased androgen synthesis. Protein-docking simulations and subsequent functional experiments suggested that the inhibitory effect of artemisinins on CYP11A1 level largely depended on their direct binding to the proteolytic domain of LONP1. Consistent with the function of artemisinins, LONP1 overexpression strongly suppressed androgen production in the ovary. Lastly, a pilot clinical trial was conducted to confirm the therapeutic effects of artemisinins in patients with PCOS. We found that dihydroartemisinin treatment effectively ameliorated hyperandrogenemia, reduced anti-Müllerian hormone levels, improved polycystic ovarian morphology, and contributed to the normalization of menstruation in patients with PCOS. CONCLUSION Our data demonstrated the efficacy of artemisinins in alleviating symptoms associated with PCOS in both rodent models and human patients. Artemisinins directly bind to LONP1, initiating the interaction between LONP1 and CYP11A1, which in turn promotes the degradation of CYP11A1, subsequently inhibiting ovarian androgen synthesis and curbing PCOS. Contrarily, androgenic inducer disrupts LONP1-CYP11A1 interaction and aggravates PCOS. Overall, our findings highlight the promising potential of artemisinins as effective drugs for the comprehensive treatment of PCOS. This discovery illuminates a previously unknown interaction between LONP1 and CYP11A1 that is enhanced by artemisinins to govern androgen synthesis, opening avenues for PCOS intervention by targeting LONP1-CYP11A1 interaction. Artemisinins inhibit ovarian androgen synthesis and relieve PCOS. The pro-androgen inducer human chorionic gonadotropin (hCG) disrupts the interaction between LONP1 and CYP11A1, leading to the up-regulation of CYP11A1, which promotes androgen production and exacerbates PCOS. Conversely, artemisinins mediate LONP1-CYP11A1 interaction, promoting the degradation of CYP11A1 and subsequently inhibiting ovarian androgen synthesis. Consequently, artemisinins show efficacy in ameliorating PCOS symptoms in both rodents and human patients [Figure created with BioRender.com ].
Type of Medium:
Online Resource
ISSN:
0036-8075
,
1095-9203
DOI:
10.1126/science.adk5382
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2024
detail.hit.zdb_id:
128410-1
detail.hit.zdb_id:
2066996-3
SSG:
11
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