Novel drug targets for the early treatment of acute pancreatitis: Focusing on calcium signaling.

Abstract

Acute pancreatitis (AP) is a common but potentially devastating disease characterized at onset pathophysiologically by premature activation of digestive enzymes within the pancreas. Despite an abundance of preclinical research and, until recently, a series of disappointing clinical trials, no specific disease modifying pharmacological treatment has yet been approved for this condition. Recent novel approaches to understanding the molecular pathogenesis of AP provide us with renewed optimism for translational drug discovery. Although digestive enzyme activation is the hallmark of AP, a critical mechanism that initiates AP is intracellular calcium (Ca²⁺) overload in pancreatic parenchymal cells, which triggers mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and impairs autophagic flux. These processes are pivotal to the disease and present a range of drug targets, associated with the inflammatory responses that drive local and systemic inflammation in AP. Progress in translation has now been made, targeting the ORAI channel with the inhibitor zegocractin (Auxora) to reduce pancreatic injury and inflammatory responses in human AP. Herein we evaluated potential drug targets for the early treatment of AP, focused on intra-acinar mechanisms of injury central to the onset and severity of AP. Our analysis highlights the opportunities and progress in translating these molecular insights into clinical therapies.