ETS1 potentiates pancreatic Pyroptosis in mice with acute pancreatitis by regulating the NKIRAS1/NF-κB Axis.

Abstract

BACKGROUND: The transcriptional regulation of pyroptosis in acute pancreatitis (AP) remains poorly understood. This study aims to elucidate the role of the transcription factor ETS proto-oncogene 1 (ETS1) and its association with pyroptosis in AP. METHODS: An AP mouse model was induced using cerulein in conjunction with lipopolysaccharide. Ets1 transgenic mice, along with the ETS1 inhibitor TK216 and the NF-κB inhibitor BAY 11-7082, were utilized for intervention. A combination of RNA sequencing, chromatin immunoprecipitation quantitative PCR, Western blotting, and immunofluorescence was employed to dissect the ETS1/NF-κB inhibitor interacting Ras-like 1 (NKIRAS1)/NF-κB signaling axis. RESULTS: ETS1 expression was significantly elevated in the pancreata of AP mice. Ets1 transgenic mice exhibited exacerbated pancreatic injury and heightened inflammation during AP. Mechanistically, ETS1 directly binds to and represses the Nkiras1 promoter, leading to decreased expression of the NF-κB inhibitor NKIRAS1. This reduction relieves the inhibition of the NF-κB pathway, thereby promoting pyroptosis and exacerbating pancreatic injury. Inhibition of ETS1 with TK216 or blockade of NF-κB signaling using BAY 11-7082 significantly mitigated pancreatic pathology and reduced the expression of key pyroptosis markers. CONCLUSIONS: This study reveals that ETS1 transcriptionally suppresses NKIRAS1, activating NF-κB signaling and promoting pyroptosis and pancreatic injury in AP. Targeting ETS1 may represent a promising therapeutic strategy.