2. Academic Validation
  3. Ascites protects against ferroptosis and enables the peritoneal growth of ovarian cancer

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

  • Nat Commun. 2026 May 11;17(1):4190. doi: 10.1038/s41467-026-72116-1.
Yasaman Setayeshpour 1 2,  Ssu-Yu Chen 3,  Divya L Dayanidhi 4,  Yunji Lee 1,  Shao-Chin Wu 1 5,  Juan J Aristizabal-Henao 6,  Jianli Wu 1,  Chao-Chieh Lin 1,  Nazanin Setayeshpour 1,  Chiara Federico 1,  Alexander A Mestre 7,  Michael A Kiebish 6,  Andrew Berchuck 8,  David S Hsu 4,  Zhiqing Huang 8,  Susan K Murphy 8,  Jen-Tsan Chi 9 10 11 12
Affiliations

Affiliations

  • 1 Department of Molecular Genetics & Microbiology, Duke University School of Medicine, Durham, NC, USA.
  • 2 Department of Cell & Molecular Biology, Duke University School of Medicine, Durham, NC, USA.
  • 3 Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
  • 4 Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
  • 5 Cancer & Immunology Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.
  • 6 BPGbio, Waltham, MA, USA.
  • 7 Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA.
  • 8 Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, NC, USA.
  • 9 Department of Molecular Genetics & Microbiology, Duke University School of Medicine, Durham, NC, USA. [email protected].
  • 10 Department of Cell & Molecular Biology, Duke University School of Medicine, Durham, NC, USA. [email protected].
  • 11 Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC, USA. [email protected].
  • 12 Center for Advanced Genomic Technologies, Duke University School of Medicine, Durham, NC, USA. [email protected].
PMID: 42115216 DOI: 10.1038/s41467-026-72116-1
Abstract

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.

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