# Ferroptosis Suppressor Protein 1 (FSP1)-CoQ10-NADPH-Axis Is Responsible for Erastin Resistance in MCF-7 Breast Cancer Cells

## TL;DR

This study identifies a new pathway involving FSP1, CoQ10, and NADPH that helps MCF-7 breast cancer cells resist a drug called erastin.

## Contribution

The study reveals a novel FSP1-CoQ10-NADPH axis as a key mechanism for erastin resistance in MCF-7 breast cancer cells.

## Key findings

- MCF-7 cells resist erastin through the FSP1-CoQ10-NADPH axis, not the usual GPX4 pathway.
- Inhibiting FSP1 makes MCF-7 cells more sensitive to erastin.
- ER downregulates FSP1 and NQO1 in MCF-7 cells but not in MCF-7/MXR cells.

## Abstract

Ferroptosis has emerged as a promising therapeutic strategy for drug-resistant cancers; however, the molecular mechanisms governing ferroptosis susceptibility in breast cancer remain poorly defined. Here, we have investigated distinct ferroptosis resistance mechanisms in parental MCF-7 breast cancer cells and their BCRP-overexpressing derivative, MCF-7/MXR. MCF-7/MXR cells displayed robust erastin (ER)-induced ferroptosis characterized by extensive lipid peroxidation, ROS accumulation, and suppression of the xCT–GSH–GPX4 axis. In contrast, MCF-7 cells were resistant to ER, exhibiting minimal lipid damage despite measurable ER-induced oxidative stress. We found that this resistance is mediated not by the canonical GPX4 pathway, but by a potent compensatory antioxidant system centered on the FSP1–CoQ10–NADPH axis. Pharmacological inhibition of FSP1 strongly sensitized MCF-7 cells to ER, with minimal effects in MXR cells. ER differentially regulated ferroptosis-associated genes, downregulating GPX4, and SLC7A11 in MXR cells but upregulating the GPX4 pathway in MCF-7 cells. Additionally, ER downregulated FSP1 and NQO1 in MCF-7 cells without affecting their expressions in MXR cells. This mechanistic divergence highlights that ferroptosis resistance in breast cancer is context-dependent and mediated by pathway-specific antioxidant programs. Co-targeting FSP1 and GPX4 therefore represents a rational strategy to overcome ferroptosis resistance in MCF-7-like breast cancers.