Adipokines, Inflammation, and Metabolic Diseases · Journal article

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

Metabolites · September 3, 2026

Promising Why this matters to you Expert discussion

Encouraging direction, but not yet definitive.

AI Summary

This study integrates transcriptomic and lipidomic analyses to identify CES1 as a key driver of lipotoxicity in hyperlipidemic acute pancreatitis and demonstrates that pharmacological CES1 inhibition (WWL113) reduces pancreatic necrosis and toxic free fatty acids in a mouse model. The work provides mechanistic proof-of-concept but lacks human clinical validation and does not yet establish efficacy as a preventive strategy in patients.

What was studied

Integrated transcriptomic, lipidomic, and in vivo mechanistic study. Transcriptomic cohorts: patients with severe acute pancreatitis and obesity/hyperlipidemia (details not specified). In vivo: P-407/caerulein-induced HAP mouse model.. Intervention: WWL113 (CES1 inhibitor) in mouse HAP model. Compared with: Untreated or control HAP-induced mice (comparator not explicitly stated).

Key findings

Three-gene signature (FASN, CES1, IL10) identified with excellent diagnostic accuracy for severe AP CES1 aberrantly upregulated and identified as primary driver of maladaptive lipolytic shift CES1 overexpression strongly correlated with neutrophil infiltration

Safety

Safety was not reported in the material analysed. Check the source before drawing any conclusion about harm.

Who this may help

This identifies CES1 as a therapeutic target and demonstrates proof-of-mechanism for a metabolism-directed intervention in HAP, but human trials are needed before clinical adoption. Clinicians should view this as foundational mechanistic work supporting further translational development rather than ready for practice implementation.

Plain-language summary

Mechanistic discovery study combining transcriptomics, lipidomics, and a validated mouse model showing proof-of-mechanism for CES1 inhibition in hyperlipidemic acute pancreatitis, but limited to preclinical validation without human efficacy data.

Study design

As stated by the source record.

MethodsPublic transcriptomic datasets of severe AP and obesity/hyperlipidemia were integrated; three machine learning algorithms identified comorbidity-associated signature genes. Mechanisms were explored via gene set variation analysis, immune infiltration profiling, and single-cell in silico knockout. In vivo validation used a P-407/caerulein-induced HAP mouse model treated with WWL113, followed by histological, biochemical, and lipidomic analyses.

DesignIntegrated transcriptomic, lipidomic, and in vivo mechanistic study

PopulationTranscriptomic cohorts: patients with severe acute pancreatitis and obesity/hyperlipidemia (details not specified). In vivo: P-407/caerulein-induced HAP mouse model.

InterventionWWL113 (CES1 inhibitor) in mouse HAP model

ComparatorUntreated or control HAP-induced mice (comparator not explicitly stated)

Reported figures

Quoted from the source exactly as published.

Diagnostic accuracy of three-gene signatureexcellent

CES1 correlation with neutrophil infiltrationstrong

Clinical bottom line

Caveats

No human efficacy data reported; findings limited to mouse model
Sample size for in vivo experiments not reported
Blinding and randomization status of animal studies not stated
No comparison of WWL113 efficacy to existing HAP prophylactic strategies

Evidence assessment

Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.

Study design

moderate

Multimodal approach combining transcriptomics, machine learning, and mouse model validation.

Directness

limited

Mouse model proof-of-concept; translational relevance to human HAP not established.

Consistency

moderate

Signature identified across public datasets; in vivo findings align with mechanistic predictions.

Risk of bias

moderate

Mouse model design not fully detailed; no statement of blinding or randomization in animal work.

Sample adequacy

insufficient

No sample size reported for mouse model or lipidomic analyses.

Source abstract

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.

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Yunshu ZhangXingchi JiangPeiyuan YinHaocheng XueJiayu LiuAdipokines, Inflammation, and Metabolic Diseases