Ascites protects against ferroptosis and enables the peritoneal growth of ovarian cancer.

The peritoneum is a frequent site of metastasis in ovarian cancer (OVCA), often accompanied by the accumulation of ascites in the peritoneal cavity. Despite its prevalence, ascites and its role in the peritoneal growth of OVCA remain poorly understood. OVCA cells are vulnerable to ferroptosis, a type of cell death caused by lipid hydroperoxides, raising the question of how these ferroptosis-sensitive cells survive during metastasis. Here, we show that ascites from female donors protects OVCA cell lines, patient-derived tumor cells, and organoids against ferroptosis and enhances peritoneal tumor growth in female mice. Mechanistically, ascites downregulates 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), contributing to increased lipid droplets. Additionally, upon ferroptosis induction, ascites represses upregulation of the transferrin receptor TFRC, thereby decreasing labile iron levels. Furthermore, lipid-lowering fibrates reverse ascites-induced changes and attenuate peritoneal growth in female mice. These findings identify ascites-mediated ferroptosis protection as a key mechanism in OVCA metastasis and a potential therapeutic vulnerability.