Exploring the Molecular Mechanisms of Phthalates in the Comorbidity of Preeclampsia and Depression by Integrating Multiple Datasets

Xinpeng Tian¹Xia Gu¹Yuecheng Yuan¹Yaqiong Zhang¹Yantuanjin Ma^2*Yingliang Liu^2*

• ¹Xichang People's Hospital, Xichang, Sichuan, China
• ²Kunming Medical University, Kunming, China

Preeclampsia (PE) and depressive disorder (DD) are clinically associated; however, their shared molecular basis remains unclear. Differential expression analysis of placental and peripheral blood transcriptomes revealed 434 secretory protein genes associated with preeclampsia. A coexpression network was constructed on the basis of depression-related datasets, yielding 1165 genes linked to major depressive disorder. Integration of protein‒protein interaction networks and functional enrichment analyses revealed immune-related pathways and extracellular matrix remodelling as common regulatory mechanisms. The machine learning algorithms selected CLEC3B, CTLA4, and PDPR as core diagnostic genes, which were subsequently validated in independent cohorts. A predictive nomogram model based on these three genes demonstrated robust diagnostic performance. Gene set enrichment analysis revealed the involvement of these genes in immune signalling pathways, including the B-cell receptor and NOD-like receptor pathways. Immune cell infiltration analysis revealed aberrant proportions of naive CD4⁺ T cells, with gene expression correlating with immune cell populations, suggesting shared immune dysregulation. Regulatory network construction revealed that multiple transcription factors modulate these genes. Molecular docking revealed stable binding interactions between the three genes and plasticizer compounds, implicating environmental factors in disease comorbidity. This study provides potential molecular evidence linking vascular dysfunction in preeclampsia with immune-related depressive pathology and offers novel targets for early diagnosis and therapeutic intervention.