Acute pancreatitis (AP) is one of the most common digestive tract diseases, but effective drug therapy is still lack. Regenerating gene protein 3 alpha (Reg3 alpha) administration significantly reduced the severity of AP in mice. HTD4010 is a new 15 amino acid long synthetic peptide and its biological activities are similar to Reg3 alpha. This study aimed to explore whether HTD4010 could protect pancreatic acinar cells against necrosis and decrease the inflammatory response in AP, and thus to explore underlying mechanisms. It was shown that administration of HTD4010 alleviated significantly the severity of biliary AP (BAP), characterized as less degree of pancreatic histological damage and acinar cell injury (both apoptosis and necroptosis), lower levels of serum amylase and pro-inflammatory cytokines. Moreover, HTD4010 down regulated the expression of toll-like receptor 4 (TLR4) protein, and TLR4 deficiency eliminated the protective effect of HTD4010 on BAP in mice. In conclusion, these results showed that HTD4010 could alleviate the severity of pancreatitis, reduce the acinar cells necrosis and inflammatory response possibly by TLR4 signaling pathway in AP. (C) 2019 Elsevier Inc. All rights reserved.