MTDH-SND1 disruption sensitizes ovarian cancer to ferroptosis and PARP inhibition

BRCA-deficient high-grade serous ovarian cancer is characterized by profound genomic instability and elevated replication-associated DNA damage, rendering these tumors initially sensitive to platinum-based chemotherapy and PARP inhibition. However, despite this vulnerability, most patients ultimately develop resistance, underscoring the need for therapeutic strategies that extend beyond DNA repair–targeted mechanisms.

Here, we introduce the MTDH–SND1 complex as a complementary therapeutic target that may expose additional stress vulnerabilities in ovarian cancer cells. We show that pharmacological disruption of the MTDH–SND1 interaction using C26-A6 increases susceptibility to ferroptosis-associated stress, an iron-dependent form of regulated cell death and that BRCA-deficient models are particularly more sensitive to this perturbation.

Notably, when combined with PARP inhibition, MTDH–SND1 disruption is associated with increased MHC class I expression in tumor cells, suggesting enhanced tumor visibility to the immune system. Together, these findings support a combination strategy that couples DNA repair disruption with metabolic and immunogenic remodeling in BRCA-deficient ovarian cancer.