The etiology of acute pancreatitis (AP) often fails to explain the severity of clinically severe acute pancreatitis (SAP). Epidemiological studies have shown that SAP is associated with obesity and abdominal fat content, and that necrotizing pancreatitis is often accompanied by peripancreatic fat necrosis, but the role of peripancreatic fat necrosis in SAP is unclear. Studies on clinical SAP humoral factors and animal models of AP have suggested the presence of multiple cytokines and increased unsaturated fatty acids (UFAs) in SAP, but the major predisposing mediators that cause exacerbation of SAP remain unclear. A study conducted by Dr. Noel et al. at Mayo Medical Center in Arizona, USA, suggests that it is peripancreatic fat necrolysis lipolysis and its production of UFAs that cause the transition from AP to SAP. the article was published in a recent Gut. The trial collected pancreatic samples (from endoscopic or surgical sources) from patients in a clinical setting, including 14 samples of pancreatic necrotic collections (NCs), 11 samples of pancreatic pseudocysts (diagnosed >3 months, PCs), and 10 samples of pancreatic cysts as controls. Cytokines elevated in NCs and PCs were extracted and interventions were performed on pancreatic blast cells and peripheral blood mononuclear cells (PBMC) cultured in vitro to observe and detect cell damage. Animal models were prepared and the interventions were performed in groups of 8-12 rats each, including the CER-only rat pancreatitis model, the CER+interleukin-1β (IL-1β) + keratinocyte chemokine/growth regulator gene protein (KC/GRO) group, the CER+triglyceride group and the CER+triglyceride + lipase inhibitor orlistat group. The results of the clinical sample study showed that the NCs were treated with a variety of drugs. Results from clinical samples showed that NCs samples contained higher levels of fatty acids, IL-8 and IL-1β compared to other samples. Lipolysis of unsaturated triglycerides produced oleic and linoleic acid components of UFAs at half the concentration in NCs to cause apoptotic necrosis of cultured cells in vitro, while other media at concentrations 2 times higher than in NCs did not have such an effect. The results of the animal model showed that the cytokine intervention resulted in increased blood amylase and lipase compared to the CER group alone, with no significant difference in the degree of increase, and increased inflammation in the pancreas and lungs of the rats. However, only 97% of the rats in the triglyceride group showed peripancreatic fat necrosis, elevated SAP-related cytokines, and elevated UFAs, as well as multiple organ failure (MSOF). This result was suppressed in the trioleic acid glycerides + orlistat group (Figure 1). Figure 1. Normal, CER-only model group, CER+IL-1β+KC/GRO group, CER+triglyceride group, and CER+triglyceride + orlistat group in order. Rats A. blood amylase B. blood lipase level, post-excision C. abdominal cavity D. pancreatic surface changes, saponified fat was visible in the abdominal cavity of the triglyceride group, while a white film on the surface of the triglyceride + orlistat group was unhydrolyzed triglyceride. The increase in blood amylase and lipase in the triglyceride group was similar to that in the other modeling groups, but the SAP expression was much more severe, which was found to be related to the activity of ascites lipase in the peritoneal cavity of rats, suggesting that it is the hydrolysis of peripancreatic fat by ascites lipase that releases UFAs and induces a systemic inflammatory response that aggravates AP, rather than being the cause of pancreatitis. Combined with the results of the existing studies, it is suggested that UFAs are directly responsible for the exacerbation of AP, while the elevation of other cytokines secondary to the elevation of UFAs may play a protective role in AP. The combined results suggest that it is not the pancreatic necrosis itself but the lipolytic effect of peripancreatic fat necrosis and its production of UFAs that causes the transition from AP to SAP, exacerbates the systemic inflammatory response and causes MSOF, leading to increased mortality. Drugs that target the inhibition of peripancreatic fat necrosis and the inhibition of UFAs production may be used to improve the prognosis of SAP, especially in the setting of obesity.