Identification of AP-1 as a Critical Regulator of Glutathione Peroxidase 4 (GPX4) Transcriptional Suppression and Acinar Cell Ferroptosis in Acute Pancreatitis.
Xiaojie MaXiaowu DongYao XuNan MaMei WeiXiaochun XieYingying LuWangsen CaoGuo-Tao LuWei-Qin LiPublished in: Antioxidants (Basel, Switzerland) (2022)
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 Gpx4 , 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 Gpx4 promoter contains a putative AP-1 binding site. Jun binds directly to the Gpx4 promoter and inhibits Gpx4 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.
Keyphrases
- transcription factor
- cell death
- dna binding
- single cell
- genome wide identification
- gene expression
- mouse model
- type diabetes
- skeletal muscle
- cell proliferation
- small molecule
- stem cells
- oxidative stress
- dna methylation
- drug delivery
- nitric oxide
- climate change
- long non coding rna
- poor prognosis
- heat stress
- artificial intelligence
- cancer therapy
- bone marrow
- endothelial cells
- replacement therapy
- heat shock