Suppression of uterine and placental ferroptosis by N-acetylcysteine in a rat model of polycystic ovary syndrome

Abstract

The mechanisms that link hyperandrogenism and insulin resistance to the increased miscarriage rate in women with polycystic ovary syndrome (PCOS) remain elusive. Previous studies demonstrate that increased uterine and placental ferroptosis is associated with oxidative stress-induced fetal loss in a pre-clinical PCOS-like rat model. Here, we investigated the efficacy and molecular mechanism of action of the antioxidant N-acetylcysteine (NAC) in reversing gravid uterine and placental ferroptosis in pregnant rats exposed to 5α-dihydrotestosterone (DHT) and insulin. Molecular and histological analyses showed that NAC attenuated DHT and insulin-induced uterine ferroptosis, including dose-dependent increases in anti-ferroptosis gene content. Changes in other molecular factors after NAC treatment were also observed in the placenta exposed to DHT and insulin, such as increased glutathione peroxidase 4 protein level. Further, increased apoptosis inducing factor mitochondria associated 2 mRNA expression was seen in the placenta but not in the uterus. Additionally, NAC was not sufficient to rescue DHT+insulin-induced mitochondria-morphological abnormalities in the uterus, whereas the same treatment partially reversed such abnormalities in the placenta. Finally, we demonstrated that NAC selectively normalized uterine leukemia inhibitory factor, osteopontin/secreted phosphoprotein 1, progesterone receptor, and homeobox A11 mRNA expression and placental estrogen related receptor beta and trophoblast specific protein alpha mRNA expression. Collectively, our data provide insight into how NAC exerts beneficial effects on differentially attenuating gravid uterine and placental ferroptosis in a PCOS-like rat model with fetal loss. These results indicate that exogenous administration of NAC represents a potential therapeutic strategy in the treatment of hyperandrogenism and insulin resistance-induced uterine and placental dysfunction.

Hydropersulfides Inhibit Lipid Peroxidation and Protect Cells from Ferroptosis

“…Despite being commonly invoked as radical-trapping antioxidants, thiols are not competent in this regard. Their reactions with peroxyl radicals are not thermodynamically favorable (essentially thermoneutral), and the kinetics (<10 3 M –1 s –1 ) are too slow to compete with chain propagation, particularly given the low concentration and/or poor solubility of most thiols in lipid bilayers. , Nevertheless, increasing the availability of thiols, for example, via treatment with N -acetylcysteine (NAC), can have an impact on cellular lipid peroxidation and the cell’s resistance to ferroptosis. − At first glance, the obvious mechanism would appear to be an increased pool of reduced glutathione, which serves as the reducing cosubstrate for the glutathione peroxidases (GPXs). However, it is plausible that other (GPX-independent) mechanism(s) contribute.…”

Bromodomains in Human-Immunodeficiency Virus-Associated Neurocognitive Disorders: A Model of Ferroptosis-Induced Neurodegeneration

“…In addition, NAC possesses anticancer and anti-HIV, properties, further linking ELS to these pathologies ( Roederer et al, 1992 ; Deng et al, 2019 ). Moreover, as NAC supplementation increases GSH and GPX, it may also suppress ferroptosis and FIN ( Karuppagounder et al, 2018 ; Hu et al, 2021 ).…”

Ferroptosis in female reproductive diseases: from potential pathogenesis to therapy

“…Of note, it was revealed by differential gene expression analysis that the interaction of autophagy, apoptosis, and ferroptosis contributed to the development of porcine ovarian atresia. 10 In addition, these ferroptosis inhibitors, Ferrostatin-1, 71 N-acetylcysteine, 72 Cryptotanshinone, 73 have shown that they can relieve symptoms in PCOS patients. Ferroptosis is generally considered to be intimately associated with the pathogenic alterations of PCOS, while the precise mechanism is still currently unclear.…”