2. Academic Validation
  3. Mechanism of LncRNA NORAD regulating ferroptosis in endometrial cancer cells by modifying GPX4 through FTO-mediated m6A methylation

Mechanism of LncRNA NORAD regulating ferroptosis in endometrial cancer cells by modifying GPX4 through FTO-mediated m6A methylation

  • Cell Mol Life Sci. 2025 Oct 25;82(1):364. doi: 10.1007/s00018-025-05855-x.
Jieqi Ke 1,  Ting Gao 1,  Zhen Shen 1,  Min Li 1,  Tianjiao Zhang 1,  Dabao Wu 2
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, No.9 Lujiang Road, Hefei, 230001, Anhui, P.R. China.
  • 2 Department of Obstetrics and Gynecology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, No.9 Lujiang Road, Hefei, 230001, Anhui, P.R. China. DabaoWu0118@163.com.
PMID: 41137882 DOI: 10.1007/s00018-025-05855-x
Abstract

Objective: Endometrial Cancer (EC) represents the most prevalent gynecologic malignancy. We probed the mechanism of long noncoding RNA activated by DNA damage (lncRNA NORAD) regulating Ferroptosis in EC cells (ECCs) by modifying Glutathione Peroxidase 4 (GPX4) through N6 methyladenosine (m6A) methylation.

Methods: The relationship between NORAD and EC clinically, and correlations of NORAD with GPX4 and fat mass and obesity-associated protein (FTO) levels were analyzed by Starbase database, Kaplan-Meier curve, and Pearson. Total m6A modification of EC tissues was detected by Dot blotting. Effects of regulating NORAD, GPX4, FTO and YTHDF2 on m6A modification and Ferroptosis in EC were explored in ECCs and nude mouse xenograft tumor models. Mechanistically, NORAD-FTO, FTO-YTHDF2 and YTHDF2-GPX4 interactions were detected by RNA pull down, Co-IP and RIP assays. GPX4 mRNA stability was determined by Actinomycin D test.

Results: NORAD was down-regulated in EC tissues and cells. Lowly-expressed NORAD in EC tissues predicted EC patients' poor prognoses, and negatively correlated with GPX4. NORAD overexpression promoted GPX4-mediated Ferroptosis. NORAD promoted ECC Ferroptosis by down-regulating GPX4. NORAD promoted YTHDF2-mediated m6A modification to reduce GPX4 mRNA stability by interacting with FTO. YTHDF2 silencing or FTO overexpression partially averted NORAD-promoted ECC Ferroptosis by modulating GPX4. NORAD promoted m6A modification to down-regulate GPX4 by interacting with FTO, and promoted Ferroptosis to inhibit tumor growth in vivo.

Conclusion: NORAD was down-regulated in EC and affected the EC prognosis. NORAD overexpression facilitated YTHDF2-mediated m6A modification by interacting with FTO to elevate GPX4 degradation, thereby stimulating ECC Ferroptosis and hindering EC progression.

Keywords

Endometrial cancer cells; FTO; Ferroptosis; GPX4; Long noncoding RNA NORAD; M6A; Methylation modification; YTHDF2.

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