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MED12 dictates epithelial ovarian cancer cell ferroptosis sensi- 2 tivity via YAP-TEAD1 signaling

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE315124 | GEO | 2026/01/01

REPOSITORIES: GEO

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Project description:Background/Objectives: Ferroptosis, an iron-dependent form of cell death, shows promise as a target for therapy-resistant cancers that exhibit increased iron metabolism. Ferroptosis is primarily characterised by lipid peroxidation within cell membranes. However, many cancers evade ferroptosis by upregulation of specialised ferroptosis defence mechanisms. This study investigates ferroptosis susceptibility in Tuberous Sclerosis Complex (TSC) cell models, and ovarian and breast cancer cell lines to identify ferroptosis resistance mechanisms and therapeutic targets. Methods: We assessed ferroptosis susceptibility using the ferroptosis inducers, RSL3 and erastin. We explored ferroptosis resistance genes using inhibitors of NRF2 (ML385) and FSP1 (iFSP1). RNA-sequencing was conducted to identify dysregulated ferroptosis resistance genes and to better characterise NRF2 target genes. RNA sequencing was also performed to identify gene expression after treatment with pro-ferroptotic iron-oxide nanoparticles. Results: TSC2-deficient cells exhibited resistance to RSL3 and erastin-induced ferroptosis, which correlated with increased ferroptosis defence gene expression, including NRF2 and downstream targets. NRF2 inhibition re-sensitised TSC2-deficient cells to ferroptosis, confirming its protective role. However, FSP1 inhibition did not re-sensitise TSC2-deficient angiomyolipoma kidney tumor cells to RSL3. In contrast, FSP1 knockdown significantly enhanced ferroptosis sensitivity in ovarian (PEO1, PEO4, OVCAR3) and breast (MDA-MB-436) cancer cell lines. Notably, in MDA-MB-436 cells, FSP1 knockdown was more effective than NRF2 inhibition in reversing ferroptosis resistance. Conclusions: Our findings highlight NRF2 and FSP1 as key regulators of ferroptosis resistance in TSC2-deficient and cancer cells. However, the differential efficacy of targeting these pathways suggests that patient stratification may be necessary for optimal therapeutic strategies. Targeting NRF2 and FSP1 could enhance ferroptosis susceptibility, offering a potential therapeutic approach for ferroptosis resistance cancers.

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MED12 dictates epithelial ovarian cancer cell ferroptosis sensi- 2 tivity via YAP-TEAD1 signaling

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