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

• الحاوية / القاعدة: Antioxidants
• المؤلفون الرئيسيون: Xiaojie Ma, Xiaowu Dong, Yao Xu, Nan Ma, Mei Wei, Xiaochun Xie, Yingying Lu, Wangsen Cao, Guotao Lu, Weiqin Li
• التنسيق: مقال
• اللغة: الإنجليزية
• منشور في: MDPI AG 2022-12-01
• الموضوعات: acute pancreatitis; ferroptosis; active protein 1; transcription factor; GPX4
• الوصول للمادة أونلاين: https://www.mdpi.com/2076-3921/12/1/100

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.