# Integrative biology shows DPP4 affects inflammatory response to eclampsia and cell model growth via p65/NLRP3/ASC/Caspase-1 pathway

## TL;DR

This study identifies DPP4 as a key player in eclampsia, showing it affects inflammation and cell growth through a specific signaling pathway, offering potential for new treatments.

## Contribution

The study reveals DPP4's role in eclampsia via the p65/NLRP3/ASC/Caspase-1 pathway, providing a novel therapeutic target.

## Key findings

- DPP4 was significantly upregulated in pre-eclampsia clinical samples and identified as a hub gene.
- DPP4 knockdown reduced pro-inflammatory cytokines and impaired trophoblast cell functions.
- The p65/NLRP3/ASC/Caspase-1 pathway was inhibited following DPP4 knockdown.

## Abstract

Objective: Eclampsia severely endangers maternal and neonatal health, being a major contributor to emergency admissions, maternal mortality, and long-term complications. This study aimed to identify reliable biomarkers and explore potential therapeutic targets for improving the diagnosis, prevention, and management of eclampsia.

Methods: Differential gene expression analysis was performed on the GSE60438 dataset. Weighted Gene Co-expression Network Analysis (WGCNA) was used to construct gene modules and screen modules associated with pre-eclampsia. Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) were employed to annotate the biological functions and pathways of candidate genes. Immune cell infiltration was evaluated via the xCell algorithm. LASSO regression was utilized to identify hub genes, which was validated by RT-qPCR and Western blot in clinical samples (placental tissues and serum from pre-eclampsia patients). DPP4 knockdown experiments were conducted in HTR-8 cells to assess its effects on pro-inflammatory cytokines (IL-6, TNF-α) and trophoblast cell functions (migration, invasion, lumen formation). Additionally, the p65/NLRP3/ASC/Caspase-1 signaling pathway was examined to clarify the underlying molecular mechanism.

Results: A total of 4,642 upregulated and 2,193 downregulated genes were identified in pre-eclampsia samples. WGCNA revealed nine gene modules, with the red module showing the strongest positive correlation and the magenta module exhibiting a negative correlation with pre-eclampsia. GO analysis indicated enrichment of candidate genes in chromosome organization, mitochondrial function, and DNA repair. GSEA identified key immune-related pathways, including cytokine production and chemokine signaling. LASSO regression pinpointed DPP4 as a hub gene, which was significantly upregulated in pre-eclampsia clinical samples. DPP4 knockdown in HTR-8 cells reduced IL-6 and TNF-α levels, impaired trophoblast migration, invasion, and lumen formation, and inhibited the phosphorylation of p65, NLRP3, ASC, and Caspase-1 in the p65/NLRP3/ASC/Caspase-1 signaling pathway.

Conclusion: Targeting DPP4 may serve as an innovative strategy for regulating inflammatory signaling in eclampsia, with potential to alleviate maternal symptoms and improve pregnancy outcomes.