MGST1 Protects Pancreatic Ductal Cells from Inflammatory Damage in Acute Pancreatitis by Inhibiting Ferroptosis: Bioinformatics Analysis with Experimental Validation

Numerous animal experiments have implicated ferroptosis in the pathogenesis of acute pancreatitis (AP). Nonetheless, due to sampling constraints, the precise role of ferroptosis in the human body during AP remains elusive. Method: Peripheral blood sequencing data of patients with acute pancreatitis (GSE194331) were obtained from the Gene Expression Omnibus (GEO) database. We analyzed differentially expressed genes whose expression increased or decreased with increasing disease severity and intersected them with the ferroptosis gene set to identify ferroptosis-related driver genes for the disease. The hub genes were selected using machine learning algorithms, and a nomogram diagnosis model was constructed. Clinical samples, animal models, and an in vitro experiment were also used for validation. The investigation unveiled 22 ferroptosis-related driver genes, and we identified three hub genes, <i>AQP3</i>, <i>TRIB2</i>, and <i>MGST1</i>, by employing two machine learning algorithms. <i>AQP3</i> and <i>TRIB2</i> exhibit robust correlations with various immune cells. The disease diagnosis model constructed utilizing these three genes demonstrated high sensitivity and specificity (AUC = 0.889). In the in vitro experiments, we discovered for the first time that ferroptosis occurs in pancreatic duct cells during acute pancreatitis, and that MGST1 is significantly upregulated in duct cells, where it plays a crucial role in negatively regulating ferroptosis via the ACSL4/GPX4 axis. In addition, overexpression of MGST1 protects ductal cells from inflammatory damage. In our investigation, we explored the mechanisms of ferroptosis in immune cells and pancreatic duct cells in patients with AP. These results highlight a potential pathway for the early diagnosis and treatment of acute pancreatitis.