Pancreatitis is a common, potentially fatal, disease of the exocrine pancreas. There are 2 major forms of pancreatitis: acute (AP), which usually produces an episode of temporary illness, and chronic (CP), associated with severe pain, poor quality of life, and increased risk for the deadliest pancreatic cancer. Pancreatitis is the third most common reason for hospital admissions in those with GI disease and a heavy burden on the U.S. healthcare system Major AP responses include inappropriate/intra-acinar activation of digestive enzymes, increased serum level of amylase, neutrophil-driven inflammation, and acinar cell death. Key pathologic features of CP are loss of acinar tissue, chronic inflammation and fibrosis, ultimately leading to the loss of exocrine and endocrine pancreatic function. It is believed that CP results from repetitive subclinical or clinically evident bouts of AP. Excessive alcohol consumption is a major risk factor for both forms of pancreatitis; other key risk factors are smoking and age. The prevalence of these factors results in high pancreatitis incidence in Veterans as well as in military personnel. The pathogenesis of pancreatitis remains obscure and no effective treatment is available, primarily because we do not understand the underlying molecular and cellular mechanisms. Recent studies indicate that the lysosomal/autophagy pathways – a key catabolic mechanism by which cells eliminate damaged or defective cytoplasmic organelles and recycle their constituents for energy and biogenesis needs – are disrupted in pancreatitis. Our recent study revealed that these pathways are critical for maintaining cholesterol homeostasis in pancreas and their disordering results in acinar cell cholesterol overload. We further showed that the cholesterol-lowering drug simvastatin alleviated experimental pancreatitis. Taken together, these findings suggest that cholesterol metabolism is a clinically relevant modulator of pancreatitis severity. To validate the role of cholesterol dysregulation in driving pancreatitis and establish cholesterol synthesis pathway as a therapeutic target amenable to pharmacologic intervention in pancreatitis, we propose to examine the effects of cholesterol- lowering drugs with different action mechanism, simvastatin and bempedoic acid (BemA), on disease severity in several dissimilar mouse and ex-vivo (cellular) pancreatitis models. These preclinical AP and CP models reflect the spectrum of disease severity and etiologies, such as excessive alcohol consumption, gallstones, and ERCP. Statins came to medical use 30 years ago; BemA, which elicits fewer adverse effects than statins, was recently approved by FDA for lowering cholesterol. The proposed studies will examine the effects of these drugs on pancreatic cholesterol levels and disease severity using various regimens of drug administration in both preventive and therapeutic modes. The Specific Aims will determine the effects of simvastatin and BemA on pancr...