PFKFB3 controls acinar IP3R-mediated Ca2+ overload to regulate acute pancreatitis severity

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Abstract
Acute pancreatitis (AP) is among the most common hospital gastrointestinal diagnoses; understanding the mechanisms underlying the severity of AP is critical for development of new treatment options for this disease. Here, we evaluate the biological function of phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in AP pathogenesis in 2 independent genetically engineered mouse models of AP. PFKFB3 was elevated in AP and severe AP (SAP), and KO of Pfkfb3 abrogated the severity of alcoholic SAP (FAEE-SAP). Using a combination of genetic, pharmacological, and molecular studies, we defined the interaction of PFKFB3 with inositol 1,4,5-trisphosphate receptor (IP3R) as a key event mediating this phenomenon. Further analysis demonstrated that the interaction between PFKFB3 and IP3R promotes FAEE-SAP severity by altering intracellular calcium homeostasis in acinar cells. Together, our results support a PFKFB3-driven mechanism controlling AP pathobiology and define this enzyme as a therapeutic target to ameliorate the severity of this condition.
Funding Information
  • the Natural Science Foundation of Jiangsu Province for Distinguished Young Scholars (BK20200004)
  • National Key Research and Development Program of China (2018YFA0900803)
  • National Natural Science Foundation of China (3217080376, 81900583, 81770630, 31870912, 31771560, 31670883, 8210140220, 81570583)
  • CAMS Innovation Fund for Medical Sciences (CIFMS2021-I2M-1-047, 2021-I2M-1-061, 2022-I2M-2-004)
  • Non-profit Central Research Institute Fund of CAMS (2019PT310028)
  • National Key Research and Development Program of China (2023YFE0118000)
  • Department of Oncology (/)
  • CAMS Innovation Fund for Medical Sciences (2023-I2M-2-010)

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