腺泡细胞的去分化是急性和慢性胰腺炎最显著的特征之一。它也可能是促进胰腺癌发展的初始步骤。在本研究中，我们进一步解析了精确机制和调控，使用了人体原代细胞和小鼠实验模型。我们的RNA测序分析表明，在两个物种中，早期腺泡细胞的去分化伴随着与细胞存活相关的多条通路的高度富集，其中SLC7A11（xCT）的表达短暂上调。xCT是胱氨酸/谷氨酸交换载体系统xC-的特异亚单位。为了解析其作用，我们使用基因沉默、药物抑制和敲除小鼠模型。xCT功能减弱或抑制的腺泡细胞显示出与脂质过氧化相关的铁死亡增加。抗氧化剂N-乙酰半胱氨酸或铁死亡抑制剂铁死亡素-1可以恢复较低的谷胱甘肽水平和更多的脂质ROS积累。在卡罗林诱导的小鼠急性胰腺炎中，xCT也能防止腺泡细胞的脂质过氧化。总之，在应激条件下，腺泡细胞命运似乎预先设定以避免多种细胞死亡形式。xCT通过提供谷胱甘肽储备和维持ROS平衡，特异性地防止腺泡细胞的铁死亡。数据表明，在应激条件下，xCT提供了一个可调控的临界点，用于引导腺泡细胞的命运。© 2023年作者。

Acinar cell dedifferentiation is one of the most notable features of acute and chronic pancreatitis. It can also be the initial step that facilitates pancreatic cancer development. In the present study, we further decipher the precise mechanisms and regulation using primary human cells and murine experimental models. Our RNAseq analysis indicates that, in both species, early acinar cell dedifferentiation is accompanied by multiple pathways related to cell survival that are highly enriched, and where SLC7A11 (xCT) is transiently upregulated. xCT is the specific subunit of the cystine/glutamate antiporter system xC-. To decipher its role, gene silencing, pharmacological inhibition and a knock-out mouse model were used. Acinar cells with depleted or reduced xCT function show an increase in ferroptosis relating to lipid peroxidation. Lower glutathione levels and more lipid ROS accumulation could be rescued by the antioxidant N-acetylcysteine or the ferroptosis inhibitor ferrostatin-1. In caerulein-induced acute pancreatitis in mice, xCT also prevents lipid peroxidation in acinar cells. In conclusion, during stress, acinar cell fate seems to be poised for avoiding several forms of cell death. xCT specifically prevents acinar cell ferroptosis by fueling the glutathione pool and maintaining ROS balance. The data suggest that xCT offers a druggable tipping point to steer the acinar cell fate in stress conditions.© 2023. The Author(s).