Identifying GSTM1, SDC1, and VTN as key biomarkers and therapeutic targets for NETs in acute pancreatitis based on bioinformatics analysis and experiments.

Abstract

Acute pancreatitis(AP) is a severe inflammatory disease associated with high morbidity and mortality. Emerging evidence suggests that neutrophil extracellular traps (NETs) play a pivotal role in AP pathogenesis; however, effective therapeutic targets and interventions remain poorly understood.We conducted weighted gene co-expression network analysis (WGCNA) on two independent transcriptomic datasets from the Gene Expression Omnibus to identify disease-associated gene modules. Differential expression analysis of NET-related genes was performed, followed by functional enrichment analysis and protein-protein interaction network construction to elucidate biological pathways. Core genes were identified using least absolute shrinkage and selection operator regression, random forest, and support vector machine recursive feature elimination algorithms. Network pharmacology was employed to predict potential therapeutic drugs. Finally, experimental validation was conducted using a caerulein-induced AP mouse and cell model.The WGCNA analysis identified 2707 key genes. Subsequently, combining differential expression analysis with machine learning approaches, we identified three core genes: glutathione S-transferase mu 1 (GSTM1), syndecan-1 (SDC1), and vitronectin (VTN). These genes exhibited significant expression alterations in AP. Drug prediction and molecular docking analysis revealed that semaxanib demonstrated strong binding affinity to all three target proteins. Experimental validation in the AP model confirmed the bioinformatics predictions: GSTM1 and VTN were significantly downregulated, while SDC1 was markedly upregulated.We identified NETs-related genes GSTM1, SDC1, and VTN as novel biomarkers for AP. Furthermore, semaxanib may have potential associations with pathways related to GSTM1, SDC1 and VTN, thereby participating to some extent in the intervention of acute pancreatitis. These findings provide a foundation for precision medicine approaches in AP management.