NOD1 induces pyroptotic cell death to aggravate liver ischemia-reperfusion injury in mice.

Nucleotide-binding oligomerization domain 1 (NOD1) can direct the release of inflammatory factors and influence autophagy and apoptosis in hepatic ischemia-reperfusion injury (IRI) in mice. As pyroptosis is involved in a number of inflammatory reactions, in this report, we investigated the potential for NOD1 to affect pyroptosis. We found that an increased expression of NOD1 during IRI was related to activation of the pyroptotic signaling pathway. With NOD1 activation, cleavage fragments of Caspase-1, gasdermin D (GSDMD), and interleukin (IL)-1β were all increased. Moreover, downregulation of NOD1 expression in AML12 cells exerted an opposite effect. Expression levels of cleaved-Caspase-1 and cleaved-GSDMD decreased after exposure to IRI and the number of cell membrane pores and apoptotic or pyroptotic cells decreased, along with the contents of inflammatory factors and lactate dehydrogenase in the supernatants of AML12 cells. Based on these findings, we conclude that NOD1 aggravates the pyroptotic cell death associated with hepatic ischemia-reperfusion injury in a mouse model via the Caspase-1/GSDMD axis. These findings help to alleviate pyroptotic cell death during liver transplantation or resection, providing new insights into novel protective therapies for liver IRI.