Endogenous tRNA-derived small RNA (tRF3-Thr-AGT) inhibits ZBP1/NLRP3 pathway-mediated cell pyroptosis to attenuate acute pancreatitis (AP)

Abstract

Endogenous transfer RNA-derived small RNAs (tsRNAs) are newly identified RNAs that are closely associated with the pathogenesis of multiple diseases, but the involvement of tsRNAs in regulating acute pancreatitis (AP) development has not been reported. In this study, we screened out a novel tsRNA, tRF3-Thr-AGT, that was aberrantly downregulated in the acinar cell line AR42J treated with sodium taurocholate (STC) and the pancreatic tissues of STC-induced AP rat models. In addition, STC treatment suppressed cell viability, induced pyroptotic cell death and cellular inflammation in AP models in vitro and in vivo. Overexpression of tRF3-Thr-AGT partially reversed STC-induced detrimental effects on the AR42J cells. Next, Z-DNA-binding protein 1 (ZBP1) was identified as the downstream target of tRF3-Thr-AGT. Interestingly, upregulation of tRF3-Thr-AGT suppressed NOD-like receptor protein 3 (NLRP3)-mediated pyroptotic cell death in STC-treated AR42J cells via degrading ZBP1. Moreover, the effects of tRF3-Thr-AGT overexpression on cell viability and inflammation in AR42J cells were abrogated by upregulating ZBP1 and NLRP3. Collectively, our data indicated that tRF3-Thr-AGT suppressed ZBP1 expressions to restrain NLRP3-mediated pyroptotic cell death and inflammation in AP models. This study, for the first time, identified the role and potential underlying mechanisms by which tRF3-Thr-AGT regulated AP pathogenesis.