NEDD4L facilitates granulosa cell ferroptosis by promoting GPX4 ubiquitination and degradation

Abstract

Background: Polycystic ovary syndrome (PCOS) is an androgen disorder and ovarian dysfunction disease in women of reproductive age. The cell death of granulosa cells plays an important role in the development of PCOS. However, the mechanism of granulosa cell death is still unclear. Methods: In the current study, NEDD4L was found to be elevated in PCOS GEO databases and mouse models. The cell viability was analyzed by CCK-8 and FDA staining. The expression of ferroptosis markers was assessed by Elisa and immunofluorescence. The direct interaction of GPX4 and NEDD4L was verified by CO-IP assay. Result: Functionally, results from CCK-8 and FDA staining demonstrated that NEDD4L inhibited the cell viability of KGN cells and NEDD4L increased the levels of iron, malonyldialdehyde (MDA), reactive oxygen species (ROS), and decreased glutathione (GSH) levels. Moreover, the cell death of KGN induced by NEDD4L was blocked by ferroptosis inhibitor, suggesting that NEDD4L regulates KGN cell ferroptosis. Mechanistically, NEDD4L directly interacts with GPX4 and promotes GPX4 ubiquitination and degradation. Conclusion: Taken together, our study indicated that NEDD4L facilitates granulosa cell ferroptosis by promoting GPX4 ubiquitination and degradation and contributes to the development of PCOS.

MiR-134-3p targets HMOX1 to inhibit ferroptosis in granulosa cells of sheep follicles

“…GSH depletion is considered a fundamental characteristic of ferroptosis [ 24 ]. Research has shown that a decrease in GSH levels promotes ferroptosis in GCs [ 25 ]. In our study investigating the regulation of oar-miR-134-3p expression, we discovered its significant negative regulation of HMOX1 expression.…”

Identification of ZIP8-induced ferroptosis as a major type of cell death in monocytes under sepsis conditions

“…However, several inducers of the degradation pathways of GPX4 could also be increased. Specifically, Mn 2+ could enhance the expression of NEDD4 like E3 ubiquitin protein ligase (NEDD4L) [ 88 ], an E3 ligase, which was recently found to mediate GPX4 degradation through ubiquitin proteasome system (UPS) [ 89 ]. Heat shock protein family A (Hsp70) member 8 (HSPA8), lysosomal associated membrane protein 2 (LAMP2A), and heat shock protein 90 (HSP90), promoting chaperone-mediated autophagy (CMA)-mediated GPX4 degradation, all could be increased by ZIP8 transported ions [ [90] , [91] , [92] , [93] , [94] , [95] , [96] , [97] ].…”

SGK1 contributes to endothelial cell ferroptosis in coronary heart disease through the NEDD4L/NF-κB pathway

“…NEDD4L belongs to the NEDD4 subfamily of ubiquitin ligases and targets a wide array of substrates, including ions, neurotransmitter channels, growth factor receptors, signaling molecules, and tight junction molecules [38] . Importantly, NEDD4L is associated with cardiovascular disease, especially coronary events [38,39] , and contributes to ferroptosis in granulocytes, cardiomyocytes, and cancer cells [27][28][29] . In this study, we observed that overexpression of NEDD4L counteracted the inhibition of ferroptosis caused by SGK1 knockdown, suggesting a regulatory relationship between SGK1 and NEDD4L in MAECs.…”

“…5D, with the minimum required interaction score set to the highest con dence level (0.9), SGK1 potentially interacts with 10 proteins, including RICTOR, MAPKAP1, MTOR, TSC22D3, PDPK1, KCNJ1, NEDD4L, FOXO3, FOXO1 and FOXO4. Notably, NEDD4L contributes to ferroptosis in multiple cell types [27][28][29] . It was hypothesized that the SGK1-mediated ferroptosis of MAECs might be associated with NEDD4L.…”