Phthalates unleashed: decoding ovarian carcinogenesis through multi-omics networks, single-cell insights, and...

Area of Science:

• Environmental toxicology
• Molecular oncology
• Computational biology

Background:

• Epidemiological studies suggest a link between phthalate exposure and ovarian cancer.
• The precise molecular mechanisms driving this association remain unclear, impeding biomarker discovery and prevention.
• This study aims to elucidate phthalate-driven oncogenic pathways using integrated computational approaches.

Purpose of the Study:

• To systematically identify molecular targets and pathways involved in phthalate-induced ovarian carcinogenesis.
• To bridge the mechanistic gap between environmental exposure and cancer development.
• To inform the development of targeted interventions and identify potential exposure biomarkers.

Main Methods:

• Network toxicology
• Multi-omics analyses (including gene expression and single-cell data)
• Molecular docking simulations

Main Results:

• Identified 234 potential phthalate targets, enriched in HIF-1 signaling and cancer-promoting metabolic pathways.
• Seven core genes were identified, with six (GAPDH, CASP3, PPARG, ESR1, CYCS, SIRT1, CCND1) differentially expressed in ovarian cancer (TCGA cohort).
• Molecular docking confirmed specific binding interactions between phthalates and six core proteins, suggesting direct molecular interference.

Conclusions:

• Phthalates may promote ovarian cancer via metabolic reprogramming (HIF-1α/glycolysis), binding to SIRT1/PPARα, and remodeling the tumor microenvironment.
• Findings establish a framework for prioritizing environmental carcinogens and identifying exposure biomarkers.
• Highlights the importance of the SIRT1-HIF1-PPARα axis in phthalate-related ovarian cancer pathogenesis and suggests reevaluation of phthalate safety.