From Plastics to Prognosis: ANO4 Susceptibility Links Phthalate Exposure to Prostate Cancer Progression

<b>Background/Objective:</b> Di-2-ethylhexyl phthalate and its bioactive metabolite mono-2-ethylhexyl phthalate (MEHP) are ubiquitous endocrine-disrupting chemicals implicated in carcinogenesis. However, the molecular mechanisms linking MEHP exposure, host genetic susceptibility, and prostate cancer progression remain incompletely defined. <b>Methods:</b> We integrated transcriptomic profiling of MEHP-exposed human prostate epithelial cells with a genetic association study of 630 patients with prostate cancer receiving androgen deprivation therapy. MEHP-responsive genes were identified from public microarray datasets and subjected to pathway enrichment analyses. Germline single-nucleotide polymorphisms (SNPs) in MEHP-regulated genes were evaluated for their association with progression-free survival, overall survival, and cancer-specific survival. The clinical and functional relevance of the key genes was further assessed using large-scale public prostate cancer expression datasets. <b>Results:</b> MEHP exposure induced widespread transcriptional reprogramming, prominently suppressing focal adhesion and cell-matrix interaction pathways. Genetic analyses identified multiple prognostically relevant SNPs within MEHP-responsive genes, with anoctamin 4 (<i>ANO4</i>) variants showing consistent associations across all clinical endpoints. The minor allele of rs17485225 in <i>ANO4</i> was significantly associated with reduced all-cause and prostate cancer-specific mortality. Pooled analyses revealed reduced <i>ANO4</i> expression levels in prostate cancer tissues and improved survival in patients with high <i>ANO4</i> expression levels. Pathway analyses linked low <i>ANO4</i> expression levels with enhanced cell cycle activity and compromised cell adhesion. <b>Conclusions:</b> Our findings suggest that <i>ANO4</i> may act as a mediator of MEHP-associated prostate cancer progression and support a gene-environment interaction model in which environmental toxicant exposure and germline variation converge on focal adhesion dysregulation to potentially contribute to aggressive disease.