Effective targeting of cancer cells has great therapeutic prospects for treating cancer. However, the effects of FTO/MKL-1/SLC7A11 on ferroptosis in breast cancer cells (MDA-MB-231 and MDA-MB-468 cell line) have not been reported so far. Therefore, we investigated how FTO deficiency triggers ferroptosis and modulates the MKL-1/SLC7A11 pathway in cancer cells.

Ferroptosis-associated events, including cell viability, GSH/GSSG ratio, and the levels of ROS and Fe ²⁺ , were detected in cancer cells with FTO overexpression or knockdown. The regulatory mechanism of FTO in the transduction of the MKL-1/SLC7A11 pathway in breast cancer cells was explored.

FTO expression was downregulated in cancer cells treated with ferroptosis inducers. FTO overexpression downregulated RSL-3-induced ferroptosis, whereas FTO deletion enhanced ferroptosis by decreasing cell viability and GSH/GSSG ratio and increasing the relative levels of ROS and Fe ²⁺ . Epitranscriptomic profiling of m6A in the breast cancer tissue of FTO knockdown (KD) and FTO overexpression (OE) mice identified MKL-1 as a target of FTO. Both MKL-1 and SLC7A11 overexpression reversed FTO deficiency-induced ferroptosis. Luciferase assay and ChIP indicated that MKL-1 targets the SLC7A11 promoter. Paclitaxel can trigger ferroptosis in MDA-MB-231 and MDA-MB-468 cell line by repressing the FTO/MKL-1/SLC7A11 axis.

These findings indicate that the FTO/MKL-1/SLC7A11 axis is a new regulatory signaling pathway for breast cancer, providing new insights into potential therapeutic targets for breast cancer.