METTL3 Promotes the Growth of Triple-Negative Breast Cancer Cells by Modulating Ferroptosis-Related Oxidative Stress via the ELF1/GPX4 Axis.

Abstract

Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited treatment options, highlighting the urgent need to identify novel therapeutic targets. The present study investigates the role of the RNA methyltransferase METTL3 in promoting TNBC progression by modulating a ferroptosis-related phenotype, an iron-dependent form of regulated cell death. Using TNBC cell lines (BT549 and MDA-MB-231), we demonstrated that METTL3 overexpression significantly enhanced cell proliferation, while its knockdown suppressed growth. Mechanistically, METTL3 was associated with decreased lipid peroxidation, reactive oxygen species (ROS), intracellular Fe^{2 +} levels, and the pro-ferroptotic protein ACSL4, alongside increased glutathione and the key ferroptosis inhibitor GPX4. Bioinformatic analysis, MeRIP-PCR, and actinomycin D chase assays indicated that METTL3 was associated with increased N⁶-methyladenosine (m6A) enrichment, expression, and persistence of ELF1 mRNA. Dual-luciferase reporter assay further suggested that ELF1 may be involved in GPX4 transcriptional regulation. Crucially, the pro-proliferative and ferroptosis-associated effects of METTL3 overexpression were partially attenuated upon ELF1 knockdown or treatment with the ferroptosis inducer erastin. In conclusion, our findings suggest a novel METTL3/ELF1/GPX4 axis through which METTL3 promotes TNBC growth by regulating oxidative stress and ferroptosis-related markers, providing a basis for further investigation of this pathway in the context of TNBC biology and therapeutic development.