Identification of AP-1 as a Critical Regulator of Glutathione Peroxidase 4 (GPX4) Transcriptional Suppression and Acinar Cell Ferroptosis in Acute Pancreatitis

• Main Authors: Xiaojie Ma (Author), Xiaowu Dong (Author), Yao Xu (Author), Nan Ma (Author), Mei Wei (Author), Xiaochun Xie (Author), Yingying Lu (Author), Wangsen Cao (Author), Guotao Lu (Author), Weiqin Li (Author)
• Format: Book
• Published: MDPI AG, 2022-12-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Glutathione peroxidase 4 (GPX4)-dependent ferroptosis in pancreatic acinar cells plays a critical role in acute pancreatitis (AP). However, potential upstream regulators of GPX4 are not well defined. Here, we observed a marked reduction in acinar GPX4 expression and ferroptotic cell death in mice with cerulein-induced AP. To determine the critical factors involved in acinar cell ferroptosis, pancreas transcriptome data from an AP mouse model were analyzed and overlapped with predicted transcription factors of <i>Gpx4</i>, and an upregulated transcription factor active protein 1 (AP-1) protein, Jun, was identified. The administration of a specific ferroptosis inhibitor liproxstatin-1 alleviated AP pathology and significantly decreased Jun levels. Bioinformatic analysis indicated that the <i>Gpx4</i> promoter contains a putative AP-1 binding site. Jun binds directly to the <i>Gpx4</i> promoter and inhibits <i>Gpx4</i> transcription under pancreatic conditions. AP-1 inhibition by a selective inhibitor SR11302 reversed GPX4 reduction and ameliorated AP pathology in a GPX4-dependent manner. Collectively, our study demonstrates that the downregulation of GPX4 by AP-1 is critical in the aggravation of acinar cell ferroptosis during the progression of AP. Strategies targeting the AP-1/GPX4 axis may be potentially effective for the prevention and treatment of AP.

Item Description

10.3390/antiox12010100
2076-3921