MED12 dictates epithelial ovarian cancer cell ferroptosis sensi-tivity via YAP-TEAD1 signaling

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy, with chem-otherapy resistance representing a major therapeutic challenge. Emerging evidence suggests that ferroptosis, an iron-dependent form of regulated cell death, may selectively target 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 in-ducers (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 expression of downstream effectors CYR61 and CTGF. Pharmacological inhi-bition of YAP with verteporfin or siRNA-mediated TEAD1 knockdown reverses ferrop-tosis 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 thera-peutic strategy in ovarian cancer. Overall design: 50,000 cells were processed using the ATAC protocol. Libraries were quantified with Bioptic Qsep100 Analyzer(Bioptic lnc.)and paired-end sequenced with read lengths of 150. The ENCODE ATAC-seq pipeline was used for quality control and statistical signal processing of short-read sequencing data, producing alignments and measures of en-richment. 150 bp paired-end reads were mapped to the reference genome build (human, hg38). Differentially sites were detected from ATAC-seq experiments using DiffBind R package.