MED12 dictates epithelial ovarian cancer cell ferroptosis sensi- 2 tivity via YAP-TEAD1 signaling
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy, with 11 chemotherapy resistance representing a major therapeutic challenge. Emerging evidence 12 suggests that ferroptosis, an iron-dependent form of regulated cell death, may selectively 13 target chemoresistant cancer cells. Here, we identify MED12 as a critical regulator of fer- 14 roptosis sensitivity in EOC through modulation of the YAP-TEAD1 signaling pathway. 15 Using CRISPR/Cas9-mediated knockout and rescue experiments in EOC cell lines, we 16 demonstrate that MED12 deficiency significantly enhances sensitivity to ferroptosis in- 17 ducers (RSL3 and Erastin), as evidenced by reduced IC50 values. Transcriptomic and 18 chromatin accessibility analyses reveal that MED12 loss activates YAP signaling through 19 TEAD1 upregulation, increasing chromatin accessibility at YAP-TEAD1 target loci and 20 elevating expression of downstream effectors CYR61 and CTGF. Pharmacological inhibi- 21 tion of YAP with verteporfin or siRNA-mediated TEAD1 knockdown reverses ferroptosis 22 sensitivity in MED12-deficient cells, confirming pathway specificity. These findings es- 23 tablish MED12 as a modulator of the YAP-TEAD1-ferroptosis axis and suggest that tar- 24 geting this pathway could overcome chemoresistance in MED12-deficient EOC. Our work 25 provides a mechanistic foundation for exploiting ferroptosis induction as a therapeutic 26 strategy in ovarian cancer. Overall design: RNAseq assay of HO8910 WT cells,  HO8910 MED12 KO1# cells and HO8910 MED12 KO2#