Mechanism of ferroptosis in a rat model of premature ovarian insufficiency induced by cisplatin

Abstract

Ferroptosis is widely present in fibrosis-related diseases. The basic pathology of premature ovarian insufficiency (POI) involves ovarian tissue fibrosis, and there are currently fewer relevant studies addressing the association between ferroptosis and POI. This study aimed to demonstrate that ferroptosis induced by cisplatin (CDDP) caused ovarian tissue fibrosis, leading to POI. Vitamin E (VE), a ferroptosis inhibitor, could repair damaged ovarian function. CDDP was used to establish a rat model of POI, and VE was administered to reverse the reproductive toxicity of CDDP. Ovarian function was assessed by histological section staining, follicle counts, sex hormone levels, as well as fertility assays. The extent of ferroptosis was assessed by transmission electron microscopy (TEM), malondialdehyde (MDA), Perls staining. CCK-8, Ethynyl-2-Deoxyuridine (EdU), and scratch assays were used to determine the effect of CDDP and VE on ovarian granulosa cell (GC) viability. Western blot, quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry were performed to evaluate ferroptosis-related molecular changes. Our results showed that CDDP caused follicle development disorders and ovarian tissue fibrosis, the levels of sex hormones suggested impaired ovarian function, and VE could reverse the reproductive toxicity of CDDP. The results of TEM, MDA and Perls staining suggested that the typical mitochondrial signature of ferroptosis was altered in ovarian GCs from the CDDP group, with significantly higher levels of lipid peroxidation and significant iron deposition in ovarian tissue, whereas VE mitigated the extent of ferroptosis. Molecular experiments then confirmed that the ferroptosis-related molecules acetyl CoA synthetase long chain family member 4 (ACSl4), 15-lipoxygenase-1 (ALOX15), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4) were differentially expressed in each group. In summary, our study preliminarily demonstrated that CDDP may promote GCs to undergo ferroptosis, cause follicle development disorders, ovarian tissue fibrosis, and induce POI by regulating the expression of ACSl4, ALOX15, SLC7A11, and GPX4, while VE improved impaired ovarian function.

Endometrial stem cells alleviate cisplatin-induced ferroptosis of granulosa cells by regulating Nrf2 expression

“…Research results confirmed cisplatin induces ovarian damage by promoting ferroptosis [ 41 ]. Another study showed ferroptosis mediates cisplatin-induced ovarian fibrosis thus leading to POF in rats [ 16 ]. We further confirm that ferroptosis is involved in the occurrence and development of POF.…”

“…Zhao et al revealed that sphingosine 1-phosphate (S1P) can alleviate radiation-induced ferroptosis in KGN cells by upregulating GPX4 expressions to restore ovarian function [ 20 ]. In addition, a previous study indicated cisplatin-induced ferroptosis mediated premature ovarian insufficiency in a rat model, and ferroptosis inhibitor Vitamin E reversed the reproductive toxic effects of cisplatin on the ovary [ 16 ]. As noted above, increasing evidence suggests that ferroptosis may contribute to the occurrence and development of POF.…”

Cyclophosphamide induces ovarian granulosa cell ferroptosis via a mechanism associated with HO-1 and ROS-mediated mitochondrial dysfunction

“…GPX4 is considered one of the principal ferroptotic markers and plays a pivotal role in the onset of ferroptosis, as its inhibition triggers lipid perxidation, leading to cellular death. Indeed, HO-1 has been shown to be a regulator of iron metabolism and antioxidant capacity, and most ferroptosis inducers could inhibit GPX4 activity directly or indirectly [ 7 ]. Conversely, Zhang et al showed that HO-1 and GPX4 were upregulated, it might suggest that HO-1 may mediate an enhanced anti-oxidative capacity in CIS-induced GC ferroptosis [ 6 ].…”

“…There is strong evidence that ROS are involved in the initiation of cell death in GC upon exposure to CTX [ 5 , 6 ]. Numerous studies have shown that POI occurs with the apoptosis of GCs, and recent work suggests ferroptosis of GCs contributes to cisplatin (CIS)-induced POI in vivo and in vitro [ 6 , 7 ]. Generally, mitochondria are particularly prone to oxidative damage, which are thought to contribute significantly to ovarian pathology [ 8 ].…”

Iron overload triggering ECM-mediated Hippo/YAP pathway in follicle development: a hypothetical model endowed with therapeutic implications

“…Du et al. reported the association between ferroptosis and POI; this is mediated by cisplatin ( 55 ). The process involves lipid peroxidation promoting ferroptosis in granulosa cells, thus causing follicle development disorders and ovarian tissue fibrosis, ultimately perturbing ovarian function and fertility ( 55 ).…”