TGM2 Aggravates Acute Pancreatitis by Impairing Macrophage Efferocytosis Through Inhibition of the STAT6–GAS6 Axis

BACKGROUND: Acute pancreatitis (AP) is characterized by dysregulated inflammation, with macrophage dysfunction (impaired efferocytosis, pro/anti-inflammatory phenotype imbalance) exacerbating the disease. Current therapies are mostly supportive, highlighting the critical need for targeted interventions. METHODS: Transglutaminase 2 (TGM2) was identified via public transcriptomic analysis. Its function was validated in caerulein-induced AP mice and in vitro cell models; mechanisms were explored via Co-IP, ChIP, and dual-luciferase assays. A lactoferrin-modified, ROS-responsive LF-LNP system was developed for TGM2 siRNA delivery. RESULTS: TGM2 was upregulated in AP; its inhibition alleviated pancreatic injury and inflammation. Mechanistically, TGM2 bound STAT6 to suppress its phosphorylation/nuclear translocation, downregulating efferocytosis-related GAS6 and impairing macrophage efferocytosis. LF-LNP@si-TGM2 targeted pancreatic macrophages, silenced TGM2, restored the STAT6-GAS6 axis, enhanced efferocytosis, and reduced inflammation. CONCLUSION: This study identifies TGM2 as a key regulator of AP macrophage efferocytosis via the novel TGM2-STAT6-GAS6 axis. LF-LNP@si-TGM2 is a promising targeted strategy for AP, potentially shifting treatment from supportive to precision therapy.