SIRT2 contributes to pancreatic injury and inflammation by modulating IER3-mediated ferroptosis in acute pancreatitis.
TL;DR
A novel SIRT2/IER3-mediated mechanism driving ferroptosis in AP is revealed, and serum SIRT2 and IER3 were elevated in AP patients and correlated with disease severity and inflammation.
Abstract
Background
Acute pancreatitis (AP) is a potentially life-threatening inflammatory disorder characterized by trypsin overactivation within acinar cells. While SIRT2 is linked to inflammation, its precise role in AP remains poorly understood.
Methods
Rats were pretreated with AGK2 (SIRT2 inhibitor), Ferrostatin-1 (Fer-1, ferroptosis inhibitor), 1α,25(OH)2D3 (IER3 inhibitor), AAV-SIRT2, or AAV-sh-SIRT2 before L-arginine-induced AP. RNA-seq was performed to identify potential downstream targets of SIRT2. In vitro, SIRT2 and IER3 expression was manipulated by siRNA or overexpression plasmids. The effects on ferroptosis and inflammation were assessed using Western blot, qPCR, immunofluorescence, and assays measuring ROS, Fe2+, mitochondrial membrane potential (MMP), and lipid peroxidation. Regulatory mechanisms among SIRT2, IER3, and ferroptosis were further investigated using co-immunoprecipitation (Co-IP) and dual-luciferase assays.
Results
AGK2 or Fer-1 alone reduced pancreatic damage, inflammation, and ferroptosis, with combination therapy showing synergy. SIRT2 or IER3 inhibition was protective, upregulating SLC7A11/GPX4, reducing ROS/Fe2+/lipid peroxides, and restoring mitochondrial function. Conversely, overexpression of SIRT2 or IER3 produced opposite effects. AGK2 and 1α,25(OH)2D3 reversed damage from SIRT2 overexpression. Co-IP confirmed SIRT2 deacetylates and upregulates IER3. Luciferase assays showed IER3 transcriptionally represses SLC7A11. Clinically, serum SIRT2 and IER3 were elevated in AP patients and correlated with disease severity and inflammation.
Conclusion
SIRT2 enhances IER3 expression via deacetylation, inhibiting the SLC7A11/GPX4 axis and promoting ferroptosis, thereby exacerbating AP. Serum SIRT2 and IER3 are potential biomarkers for AP severity. This study reveals a novel SIRT2/IER3-mediated mechanism driving ferroptosis in AP.