Nesfatin‐1 Ameliorates Acute Pancreatitis by Inhibiting the Pyroptosis of Acinar Cells and Inflammation Mediated by Macrophages and Neutrophils

Acute pancreatitis (AP) is an inflammatory disorder with no efficient therapy. Here we demonstrate that the anorexigenic peptide nesfatin-1 exerts potent and dose-dependent protection against both caerulein-induced and hypertriglyceridemic AP. Intraperitoneal administration of nesfatin-1 to restore its serum levels significantly reduced pancreatic necrosis, edema, and infiltration of immune cells, as well as circulating levels of amylase, lipase, and pro-inflammatory cytokines. RNA-seq revealed that nesfatin-1 down-regulated the ER-stress signature (Ddit3, Atf3, Ppp1r15a) and the NF-κB/NLRP3 signaling. Further studies in primary acinar cells confirmed that nesfatin-1 at the dose of 10 nM suppressed phosphorylated eIF2α, DDIT3, ATF3, p65, and NLRP3, thereby inhibiting pyroptosis. Consequently, nesfatin-1 attenuated macrophage/neutrophil infiltration, shifted M1 toward M2 macrophages, inhibited the release of inflammatory cytokines, and alleviated multi-organ injury in lung, intestine, and spleen. Collectively, nesfatin-1 limits AP severity by restraining ER-stress-driven pyroptosis and innate immune activation. Thus, nesfatin-1 may serve as a promising therapeutic candidate for acute pancreatitis.