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Pancreatic cancer (PC) is an almost uniformly lethal disease with inflammation playing an important role in its progression. Sustained stimulation of purinergic receptor P2X7 drives induction of NLRP inflammasome activation. To understand the role of P2X7 receptor and inflammasome, we performed transcriptomic analysis of p48 Cre/+-LSL-Kras G12D/+ mice pancreatic tumors by next generation sequencing. Results showed that P2X7R's key inflammasome components, IL-1β and caspase-1 are highly expressed (p< 0.05) in pancreatic tumors. Hence, to target P2X7R, we tested effects of two P2X7R antagonists, A438079 and AZ10606120, on pancreatic intraepithelial neoplasms (PanINs) and their progression to PC in p48 Cre/+-LSL-Kras G12D/+ mice. Following dose optimization studies, for chemoprevention efficacy, six-week-old p48 Cre/+-LSL-Kras G12D/+ mice (24–36/group) were fed modified AIN-76A …