PhIP-driven prostate cancer involves key molecular regulators and immune microenvironment modulation.

Area of Science:

• Oncology
• Toxicology
• Bioinformatics

Background:

• 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) exposure is suspected to promote prostate cancer (PCa) development.
• The exact molecular mechanisms underlying PhIP's role in PCa remain largely unknown.

Purpose of the Study:

• To identify molecular targets of PhIP in PCa using integrated network toxicology, bioinformatics, and machine learning.
• To evaluate the biological significance of identified targets through various analyses and experimental validation.

Main Methods:

• Network toxicology, bioinformatics, and machine learning algorithms were employed to identify candidate genes.
• Molecular docking, molecular dynamics simulations, and experimental validation were used to assess target interactions and effects.
• Immune infiltration and single-cell analyses were performed to understand the tumor microenvironment context.

Main Results:

• 17 candidate genes linked to PhIP-induced PCa were identified, with SLC14A1 highlighted as a key contributor.
• PhIP demonstrated a stable, high-affinity complex with SLC14A1 and induced cytotoxicity.
• PhIP exposure correlated with reduced SLC14A1 expression and was associated with the tumor immune microenvironment and epithelial localization.

Conclusions:

• PhIP exposure presents potential risks for PCa initiation and progression.
• Identified genes and pathways, particularly SLC14A1, may serve as novel biomarkers and therapeutic targets for PCa.
• Findings provide new directions for PCa research and public health strategies concerning PhIP exposure.