Integrating Single-Cell Sequencing, Machine Learning, and Molecular Docking to Elucidate the Molecular Network...

Area of Science:

• Environmental Health
• Cardiovascular Biology
• Immunology

Background:

• Di-(2-ethylhexyl) phthalate (DEHP) is a common plasticizer linked to cardiovascular dysfunction and myocardial infarction (MI).
• The specific molecular mechanisms by which DEHP exacerbates MI, particularly within immune cells, are not well understood.

Purpose of the Study:

• To identify and validate DEHP-specific molecular mechanisms in immune cells contributing to MI pathogenesis.
• To integrate machine learning, single-cell RNA sequencing, and molecular docking to uncover DEHP-immune cell-MI links.

Main Methods:

• Integrated analysis of transcriptomic datasets and DEHP target prediction.
• Machine learning algorithms for prioritizing shared DEHP-MI targets.
• Immune cell profiling (CIBERSORT) and spatial validation (scRNA-seq) of core genes.
• Molecular docking simulations to assess DEHP-target binding.

Main Results:

• Identified 56 shared DEHP-MI targets involved in innate immune activation and chemotaxis.
• Prioritized six core genes (SLC2A3, MMP9, AKR1C3, DAPK2, MAP3K8, TRIB1) as diagnostic biomarkers for MI (AUC=0.981), with SLC2A3 and MMP9 as key drivers.
• DEHP directly binds to SLC2A3 and MMP9, promoting pro-inflammatory immune dysregulation, including neutrophil recruitment and M0 macrophage polarization.
• DEHP exacerbates MI via cell-type-specific mechanisms, affecting monocytes and NK cells.

Conclusions:

• DEHP exacerbates MI by directly binding to immune cell targets, leading to pro-inflammatory immune dysregulation.
• Identified novel cell-type-specific pathogenic mechanisms involving monocytes and NK cells in DEHP-induced cardiotoxicity.
• The study provides potential therapeutic targets for mitigating DEHP-related cardiovascular damage.