Disulfiram Mitigates Acinar Cell Damage in the Caerulein-Induced Acute Pancreatitis Model through Inhibition of the NLRP3/Caspase-1/GSDMD Pathway

Acute pancreatitis (AP) is marked by severe inflammatory injury to pancreatic acinar cells, with pyroptosis playing a critical role in its progression.Disulfiram (DSF), traditionally prescribed for alcohol dependence, has recently attracted attention for its anti-inflammatory potential.In this study, caerulein-stimulated AR42J cells were used to model AP in vitro and to evaluate whether DSF could alleviate cellular injury and inflammatory responses.Treatment with DSF improved cell viability, suppressed lactate dehydrogenase release, and significantly reduced pro-inflammatory cytokines IL-1 and IL-18.Mechanistic analyses revealed that DSF downregulated NLRP3, cleaved Caspase-1, and the active fragment of GSDMD, indicating inhibition of the NLRP3/Caspase-1/GSDMD pyroptotic pathway.Additional experiments showed that pharmacological inhibition of Caspase-1 enhanced the beneficial effects of DSF, while GSDMD overexpression counteracted them, confirming the centrality of this pathway to DSF's protective action.These findings suggest that DSF modulates inflammasomedriven pyroptotic signaling in pancreatic acinar cells under inflammatory conditions and may warrant further investigation in more complex in vivo models of acute pancreatitis.