Network toxicology and cell experiments reveal the mechanism of DEHP-induced diabetic nephropathy via Wnt signaling pathway.

Di(2-ethylhexyl) phthalate (DEHP), a widely recognized endocrine disruptor, has been linked to the pathogenesis of diabetic nephropathy (DN) through its interference with hormonal and metabolic homeostasis. This study integrates network toxicology with cell-based assays to elucidate the molecular mechanisms of DEHP-induced DN, seeking to identify novel targets for toxicity assessment and therapeutic intervention. Through comprehensive screening across multiple toxicology and disease-related databases, six core genes (CTNNB1, EGFR, TNF, CCND1, BCL2, CASP3) were identified as shared mediators of DEHP exposure and DN. These genes are predominantly associated with the Wnt signaling pathway, a pivotal regulator of podocyte function, including cellular adhesion, differentiation, apoptosis, and inflammatory response. Mouse glomerular podocytes (MPC-5) exposed to graded concentrations of DEHP, with or without the Wnt pathway inhibitor XAV-939, displayed significant DEHP-induced disruptions: reduced cell adhesion, proliferation, and differentiation; increased autophagy, apoptosis, and migratory activity; elevated inflammatory mediator release; and pronounced activation of the Wnt signaling pathway, evidenced by upregulation of β-catenin, EGFR, TNF, CCND1, BCL2 and downregulation of CASP3. DEHP exposure further altered transcriptional activity and chromatin structure at key loci (CTNNB1, EGFR, and TNF). XAV-939 effectively mitigated these effects, underscoring the Wnt pathway's central role in DN progression under DEHP influence. These findings highlight the complex multi-target, multi-pathway interactions of DEHP in DN pathophysiology, offering deeper mechanistic insights and potential targets for therapeutic intervention against DEHP-induced nephrotoxicity.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
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