Nuclear protein 1 defends against acute pancreatitis by mitigating pancreatic acinar cell ferroptosis through the maintenance of cellular iron homeostasis.

Abstract

Acute pancreatitis (AP) is a severe inflammatory condition marked by pancreatic acinar cell death, with ferroptosis emerging as a critical factor in its pathogenesis. The nuclear protein 1 (Nupr1) has been identified as a key regulator of ferroptosis; however, its role in modulating pancreatic acinar cell ferroptosis and its involvement in AP remain unexplored. The objective of this research was to examine whether Nupr1 regulates ferroptosis in pancreatic acinar cells and influences the progression of AP, while elucidating the underlying molecular mechanisms. Nupr1 was significantly upregulated in caerulein-induced AP models. Nupr1 knockdown pancreatic acinar cells exhibited heightened susceptibility to caerulein-induced damage and inflammatory responses, accompanied by elevated levels of ferroptosis. Conversely, overexpression of Nupr1 conferred resistance against caerulein-induced injury, inflammation, and ferroptosis. Inhibition of ferroptosis reversed the sensitivity of Nupr1 knockdown cells to caerulein-induced damage. Further investigations revealed that Nupr1 regulates the expression of lipocalin 2 (Lcn2), thereby maintaining intracellular iron homeostasis. Silencing Lcn2 negated the protective effects of Nupr1 overexpression in pancreatic acinar cells against ferroptosis. In animal models, Nupr1 overexpression significantly attenuated the progression of AP and reduced ferroptotic levels in pancreatic tissues. Collectively, our findings demonstrate that Nupr1 inhibits pancreatic acinar cell ferroptosis by regulating Lcn2-mediated iron homeostasis, thereby mitigating the progression of AP. This research reveals a previously unidentified regulatory mechanism governing acinar cell death in AP and suggests a possible therapeutic target for managing this condition.