Signaling Pathways Involved in Acute Pancreatitis

Abstract

Acute pancreatitis (AP) is a common digestive emergency with high morbidity and mortality. Over the past decade, significant progress has been made in understanding the mechanisms of AP, including oxidative stress, disruptions in calcium homeostasis, endoplasmic reticulum stress, inflammatory responses, and various forms of cell death. This review provides an overview of the typical signaling pathways involved and proposes the latest clinical translation prospects. These strategies are important for the early management of AP, preventing multi-organ injury, and improving the overall prognosis of the disease.

Keywords: acute pancreatitis; calcium overload; cell death; endoplasmic reticulum stress; signaling pathway.

Figure 1

Calcium-mediated mitochondrial dysfunction and cell death in AP. In acinar cells, Piezo1 is a mechanosensitive receptor with cation channel properties, which is activated under conditions of increased pressure in the pancreatic ducts, promoting extracellular Ca²⁺ influx (1). High levels of cholecystokinin (CCK), alcohol, and bile acids lead to the release of calcium from the endoplasmic reticulum through IP3R and RyR-mediated pathways (2). The decrease in Ca²⁺ levels within the endoplasmic reticulum triggers the opening of Orai1, facilitating extracellular Ca²⁺ influx (3). This results in pathological elevation of calcium ions. The increase in calcium ion concentration leads to sustained opening of the mitochondrial permeability transition pore (mPTP), causing loss of the mitochondrial membrane potential [1]. This process leads to mitochondrial dysfunction, ATP depletion, and oxidative stress. These events further enhance and perpetuate pathological calcium toxicity, leading to the occurrence of other pathological processes, such as abnormal activation of trypsinogen [2], activation of inflammatory pathways [3], impaired calcium reuptake [4], and calcium efflux defects [5].

Figure 2

UPR Pathways act in AP. In acinar cells, pathological events such as abnormal enzyme activation, oxidative stress, calcium overload, and mitochondrial dysfunction all lead to an increased demand for protein synthesis. Meanwhile, alcohol, fatty acids, and other AP-related toxins act on acinar cells. These activities induce endoplasmic reticulum (ER) stress. This stress occurs when the demand for protein synthesis and the accumulation of misfolded or unfolded proteins exceed the ER’s capacity to process them. IRE1, ATF6, and PERK sense misfolded proteins in the ER lumen. The effector protein of IRE1 splices X-box binding protein 1 (XBP1) to form spliced XBP1 (sXBP1). ATF6, under the action of the S1/2P protease complex in the Golgi, forms cleaved ATF6 (cATF6). These are transcription factors involved in ER expansion, molecular chaperone processes, and ER-associated degradation (ERAD), allowing the ER to restore its protein processing capacity. In extreme ER stress conditions, the three UPR pathways lead to apoptosis and inflammation mediated by CEBP homologous protein (CHOP).

Figure 3

IL-22 mediates tissue regeneration and anti-infection through JAK/STAT pathway in AP.