Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026
TGM2 Aggravates Acute Pancreatitis by Impairing Macrophage Efferocytosis Through Inhibition of the STAT6-GAS6 Axis.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
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Liu Xuxu, Du Zhiwei, Wang Liyi, Xie Zhihong, Meng Ziang, Zheng Yi, Wang Heming, He Yuanhang, Xue Dongbo
Аннотация
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.
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.