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

ABSTRACT 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.