Abstract One of the most common sites of metastasis in ovarian cancer (OVCA) is the peritoneum. Often, this spread is accompanied by the accumulation of a fluid called ascites in the peritoneal cavity. Despite its common occurrence in metastatic OVCA patients, ascites and its influence on the peritoneal spread of OVCA are poorly understood. Interestingly, OVCA cells are vulnerable to ferroptosis, a type of cell death caused by lipid hydroperoxides. Hence, how these ferroptosis-sensitive OVCA cells persist in their spread to the peritoneum remains unknown. Here, we show that ascites robustly protects OVCA cell lines, patient-derived tumor cells and organoids against ferroptosis and enhances the peritoneal spread of OVCA cells in mice. Mechanistically, ascites downregulates the mitochondrial enzyme, 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), which contributes to an increase in lipid droplets. Additionally, upon ferroptosis induction, ascites represses the upregulation of the transferrin receptor, TFRC, thereby decreasing cellular labile iron levels. Furthermore, we show that lipid-lowering fibrates reverse cellular changes induced by ascites, and they attenuate the peritoneal spread of OVCA cells in mice. Our findings implicate the importance of ascites in ferroptosis protection and the peritoneal spread of OVCA, and they suggest that targeting the ferroptosis protection by ascites may present a novel therapeutic approach to limit OVCA metastasis. Citation Format: Yasaman Setayeshpour, Ssu-Yu Chen, Divya L. Dayanidhi, Yunji Lee, Shao-Chin Wu, Juan J. Aristizabal-Henao, Jianli Wu, Chao Chieh (Jerry) Lin, Nazanin Setayeshpour, Chiara Federico, Alexander A. Mestre, Michael A. Kiebish, Andrew Berchuck, David S. Hsu, Zhiqing Huang, Susan K. Murphy, Jen-Tsan Ashley Chi. Ascites protects against ferroptosis and enables the peritoneal spread of ovarian cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4803.
Setayeshpour et al. (Fri,) studied this question.