Cellular and molecular life sciences : CMLSOct 25, 2025

How a Specific RNA Affects Cell Death in Endometrial Cancer

Updated Jan 2, 2026

Abstract

NORAD was down-regulated in endometrial cancer tissues and cells.

Low expression levels of NORAD in endometrial cancer tissues are associated with poor patient prognoses.
NORAD overexpression enhances ferroptosis in endometrial cancer cells by promoting the degradation of GPX4.
NORAD interacts with FTO to facilitate m6A modification, which reduces GPX4 mRNA stability.
Silencing YTHDF2 or overexpressing FTO can partially reverse the ferroptosis promoted by NORAD in endometrial cancer cells.
The findings suggest that NORAD may play a crucial role in regulating tumor growth through ferroptosis in endometrial cancer.

Simplified

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.

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Declarations. Ethical approval: The study was approved by the Ethics Committee of The First Affiliated Hospital of USTC. All sample collection and data investigation procedures were conducted following the principles of the Declaration of Helsinki, with signed informed consent obtained from patients and their families. All animal experiments in this study were reviewed and ratified by the Animal Ethics Committee of The First Affiliated Hospital of USTC. Consent for publication: Not applicable. Competing interests: The authors have no conflicts of interest to declare. Submission declaration and verification: The work described has not been published previously, that it is not under consideration for publication elsewhere, that its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out, and that, if accepted, it will not be published elsewhere in the same form, in English or in any other language, including electronically without the written consent of the copyright-holder.

PubMed

Abstract

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Competing interests

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