# MED12 Dictates Epithelial Ovarian Cancer Cell Ferroptosis Sensitivity via YAP–TEAD1 Signaling

## TL;DR

This study shows that MED12 influences the sensitivity of ovarian cancer cells to a type of cell death called ferroptosis through the YAP–TEAD1 signaling pathway.

## Contribution

The paper identifies MED12 as a novel regulator of ferroptosis sensitivity in epithelial ovarian cancer via YAP–TEAD1 signaling.

## Key findings

- MED12 deficiency increases sensitivity to ferroptosis inducers in ovarian cancer cells.
- Loss of MED12 activates YAP signaling through TEAD1 upregulation, enhancing chromatin accessibility and downstream gene expression.
- Inhibiting YAP or TEAD1 reverses ferroptosis sensitivity in MED12-deficient cells, confirming pathway specificity.

## Abstract

Epithelial ovarian cancer (EOC) represents the most lethal malignancy arising from the female reproductive tract, largely due to the clinical challenge of chemotherapy resistance. Recent studies indicate that ferroptosis—a distinct form of programmed cell death driven by iron accumulation and lipid peroxidation, could potentially exploit a vulnerability in chemoresistant cancer cells. Here, we identify MED12 as a critical regulator of ferroptosis sensitivity in EOC through modulation of the YAP–TEAD1 signaling pathway. Using CRISPR/Cas9-mediated knockout and rescue experiments in EOC cell lines, we demonstrate that MED12 deficiency significantly enhances sensitivity to ferroptosis inducers (RSL3 and Erastin), as evidenced by reduced IC50 values. Transcriptomic and chromatin accessibility analyses reveal that MED12 loss activates YAP signaling through TEAD1 upregulation, increasing chromatin accessibility at YAP–TEAD1 target loci and elevating the expression of downstream effectors CYR61 and CTGF. Pharmacological inhibition of YAP with verteporfin or siRNA-mediated TEAD1 knockdown reverses ferroptosis sensitivity in MED12-deficient cells, confirming pathway specificity. These findings establish MED12 as a modulator of the YAP–TEAD1–ferroptosis axis and suggest that targeting this pathway could overcome chemoresistance in MED12-deficient EOC. Our work provides a mechanistic foundation for exploiting ferroptosis induction as a therapeutic strategy in ovarian cancer.