What question did this study set out to answer?

This research aims to understand how ascites influences the survival of ovarian cancer cells during peritoneal metastasis and their vulnerability to ferroptosis.

April 5, 2026

Abstract 4803: Ascites protects against ferroptosis and enables the peritoneal spread of ovarian cancer

Key Points

This research aims to understand how ascites influences the survival of ovarian cancer cells during peritoneal metastasis and their vulnerability to ferroptosis.
Utilized OVCA cell lines, patient-derived tumor cells, and organoids to test the effects of ascites.
Assessed the role of ascites in ferroptosis protection through mitochondrial enzyme regulation.
Evaluated the impact of lipid-lowering fibrates on peritoneal spread of OVCA in mice.
Ascites significantly protects OVCA cells from ferroptosis, facilitating their spread in the peritoneum.
Ascites downregulates HMGCS2, leading to increased lipid droplet formation.
Exposure to ascites reduces transferrin receptor expression, lowering cellular labile iron levels.
Lipid-lowering fibrates reverse the protective effects of ascites and reduce OVCA peritoneal spread.

Abstract

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.

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Cite This Study

Setayeshpour et al. (Fri,) studied this question.

synapsesocial.com/papers/69d1fcfda79560c99a0a2beb https://doi.org/https://doi.org/10.1158/1538-7445.am2026-4803

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