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. 2024 Dec;55(6):1163-1175.
doi: 10.1007/s10735-024-10257-7. Epub 2024 Sep 11.

METTL3 silencing inhibits ferroptosis to suppress ovarian fibrosis in PCOS by upregulating m6A modification of GPX4

Chuan Shen  1   2 , Yongmei Jiang  2 , Jia Lin  1 , Qiwei Guo  1 , Dingzhi Fang  3
Affiliations

METTL3 silencing inhibits ferroptosis to suppress ovarian fibrosis in PCOS by upregulating m6A modification of GPX4

Chuan Shen et al. J Mol Histol. 2024 Dec.

Abstract

Methyltransferase-like 3 (METTL3) is extensively reported to be involved in organ fibrosis. Ovarian fibrosis is a main characteristic of polycystic ovary syndrome (PCOS). However, the reaction mechanism of METTL3 in PCOS is poorly investigated. This paper was intended to reveal the role and the mechanism of METTL3 in PCOS. Animal and cell models of PCOS were induced by dehydroepiandrosterone (DHEA). H&E staining was performed to detect the pathological alterations in ovary tissues. Masson staining, immunofluorescence, along with western blot measured fibrosis both in vitro and in vivo. To evaluate estrous cycle, vaginal smear was performed. Lipid peroxidation and ferroptosis were evaluated by MDA assay kits, GSH assay kits, immunohistochemistry, Prussian blue staining and western blot. qRT-PCR and western blot were adopted to estimate METTL3 and GPX4 expression. The m6A and hormone secretion levels were respectively assessed by m6A RNA Methylation Quantitative Kit and corresponding kits. The interaction between METTL3 and GPX4 was testified by immunoprecipitation. The fibrosis and ferroptosis were aggravated and m6A and METTL3 expression were increased in ovarian tissues of DHEA-induced PCOS mice. METTL3 silencing alleviated pathological changes, affected hormone secretion level, and repressed fibrosis, lipid peroxidation and ferroptosis in the ovarian tissues of PCOS mice. In vitro, DHEA stimulation increased m6A and METTL3 expression and induced ferroptosis and fibrosis. METTL3 knockdown promoted GPX4 expression in DHEA-induced granulosa cells by m6A modification and restrained DHEA-induced fibrosis, lipid peroxidation and ferroptosis in granulosa cells via elevating GPX4. METTL3 silence inhibited ovarian fibrosis in PCOS, which was mediated through suppressing ferroptosis by upregulating GPX4 in m6A-dependent manner.

Keywords: GPX4; METTL3; Ovarian fibrosis; Polycystic ovary syndrome (PCOS); m6A.

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Conflict of interest statement

Declarations Competing interests The authors declare no competing interests.

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