Shared Genetic Risk Between Acute Pancreatitis and Metabolic Syndrome Converges on a BCAT1-Positive Fibroblast...

Area of Science:

• Genetics and Genomics
• Molecular Biology
• Systems Biology

Background:

• Metabolic syndrome (MetS) is linked to increased acute pancreatitis (AP) severity.
• Understanding the shared genetic basis and molecular mechanisms is crucial for developing targeted therapies.

Purpose of the Study:

• To identify shared differentially expressed genes (CDEGs) between MetS and AP.
• To prioritize mechanistically relevant genes and potential therapeutic targets for severe AP (SAP).

Main Methods:

• Utilized linkage disequilibrium score regression (LDSC) and Mendelian randomization (MR) to assess genetic correlation and causality.
• Analyzed Gene Expression Omnibus (GEO) datasets to identify CDEGs and AP hub genes (AP-HGs) via functional enrichment and protein-protein interaction (PPI) analysis.
• Employed GeneMANIA, MR, and single-cell RNA sequencing (scRNA-seq) for functional validation, followed by computational drug prediction and molecular docking.

Main Results:

• Confirmed a positive genetic correlation and causal effect of MetS on AP risk.
• Identified BCAT1, GPAT3, ANP32C, and ZNF683 as CDEGs; MAPK14 emerged as a central AP-HG.
• MAPK14, BCAT1, and GPAT3 showed predictive value for SAP. scRNA-seq localized Mapk14 to macrophages and Bcat1 to proliferative fibroblasts.
• Validated findings in a hyperlipidemia AP (HAP) model, showing aggravated pancreatic injury and BCAT1/MAPK14 upregulation.

Conclusions:

• Established a genetic and transcriptomic link between MetS and AP.
• MAPK14-driven inflammation and BCAT1-mediated fibroblast remodeling may worsen AP under metabolic stress.
• BCAT1 and MAPK14 are promising mechanistic targets, with Ozagrel as a potential therapeutic candidate.