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Autophagy is a cellular degradative process driven by the lysosomal pathway and is an essential mechanism by means of which cells remove dysfunctional components, allowing cellular organelle recycling. The exact role of autophagy in the pathogenesis of AP remains unclear [50], although impaired autophagy (mainly macroautophagy) has been defined as a critical pathological event during the early phase of AP [13,51–53], significantly aided by the recent comprehensive demonstration of methods to identify autophagic structures and to measure autophagic flux using in vitro and in vivo models of pancreatitis [54]. The investigation of autophagy in AP began a decade ago when Yamamura and colleagues [55,56] created a conditional knockout mouse lacking the autophagy‐related gene Atg5 in pancreatic acinar cells and found the severity of cerulein‐induced AP to be significantly alleviated in vivo. Furthermore, isolated acinar cells from these mice showed a greatly reduced level of cerulein‐induced trypsinogen activation. Vitamin K₃ administration can markedly attenuate cerulein‐induced AP by inhibition of microtubule‐associated protein 1A/1B‐light chain 3 (LC3‐II) expression and colocalization of autophagosomes and lysosomes in pancreatic tissue [57]. Blocking autophagic flux with a specific inhibitor, 3‐methyladenine, substantially prevented cell vacuolation and trypsinogen activation induced by CCK hyperstimulation of mouse pancreatic acinar cells [53] and alleviated cerulein plus lipopolysaccharide‐induced pancreatic injury alongside multiple organ failure [58]. Treatment with CYT387, a TBK1‐mediated autophagy inhibitor, significantly suppressed cytokine activation and pancreatic inflammatory cell infiltration in cerulein‐induced mouse AP [59]. Most recently, trehalose, an mTOR‐independent autophagy enhancer, has been demonstrated to alleviate experimental AP in the L‐arginine and cerulein models of AP by reducing the accumulation of LC3‐II, P62 and other ubiquitinated proteins, accumulation of which occurs as a result of impaired autophagic flux [60,61] (see Figure 12.1). Simvastatin may also play a protective role in AP through the modulation of autophagy [62]. Future focus on specific “clean” agents that maintain an efficient and healthy autophagic pathway for pancreatic acinar cells may be of potential use for the treatment of AP.