Integrated Transcriptomics and Lipidomics Identify CES1-Mediated Maladaptive Lipolysis as a Key Target of Hyperlipidemic Acute Pancreatitis.

BACKGROUND: Hyperlipidemic acute pancreatitis (HAP) is a severe disease driven by systemic lipid overload. While free fatty acids (FFAs) are known to mediate pancreatic lipotoxicity, the intracellular enzymatic mechanisms generating these toxic lipid mediators remain unclear. We aimed to identify the core metabolic drivers linking systemic hyperlipidemia to local pancreatic injury and evaluate targeted prophylactic strategies for HAP. METHODS: We integrated public transcriptomic datasets of severe AP and obesity/hyperlipidemia. Three machine learning algorithms were employed to identify comorbidity-associated signature genes. The underlying mechanisms were explored via gene set variation analysis, immune infiltration profiling, and single-cell in silico knockout. In vivo validation was performed using a P-407/caerulein-induced HAP mouse model treated with WWL113, followed by comprehensive histological, biochemical, and lipidomic analyses. RESULTS: A robust three-gene signature (FASN, CES1, IL10) was identified with excellent diagnostic accuracy. Notably, within this signature, the triglyceride hydrolase CES1 was aberrantly upregulated, serving as the primary driver of a maladaptive lipolytic shift. CES1 overexpression was strongly correlated with neutrophil infiltration. Single-cell virtual knockout suggested a potential association between Ces1d and markers of endothelial barrier disruption and neutrophil chemotaxis. In vivo, WWL113 significantly attenuated HAP-induced pancreatic necrosis and systemic inflammation. Crucially, lipidomics confirmed that WWL113 sequestered exogenous lipids in inert triglyceride states, drastically reducing toxic FFAs. CONCLUSIONS: This study highlights CES1 as a critical intracellular mediator of lipotoxicity in HAP. Pharmacological inhibition of CES1 effectively halts maladaptive lipolysis, providing proof-of-mechanism for a metabolism-directed prophylactic strategy for HAP.