Pancreatic acinar cell fate relies on system xc- to prevent ferroptosis during stress

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 mechanism and regulation using murine experimental models. Our RNAseq analysis indicates that, 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-. 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. Overall design: Fresh isolated pancreatic acinar cells of WT or xCT KO mouse were cultured in vitro to allow dedifferentiation. Samples were collected at day0, day1 and day4. For each timepoint, 3 biological replicates were examined. Comparative gene expression profiling analysis of RNA-Seq data between genotypes and among differnet timepoints were performed.

腺泡细胞去分化是急性与慢性胰腺炎最显著的特征之一，同时亦是推动胰腺癌发生发展的初始环节。本研究借助小鼠实验模型，进一步解析了其精确的调控机制。
我们的RNA测序（RNA-seq）分析显示，腺泡细胞早期去分化阶段伴随多个与细胞存活相关的通路显著富集，其中SLC7A11（xCT）的表达呈现瞬时上调。xCT是胱氨酸/谷氨酸反向转运体系统xC-的特异性亚基。
xCT功能缺失或降低的腺泡细胞，其铁死亡（ferroptosis）水平升高，且该过程与脂质过氧化密切相关。谷胱甘肽水平降低以及脂质活性氧（ROS，Reactive Oxygen Species）积累增多的表型，可通过抗氧化剂N-乙酰半胱氨酸（N-acetylcysteine）或铁死亡抑制剂Ferrostatin-1得到逆转。
在雨蛙素（caerulein）诱导的小鼠急性胰腺炎模型中，xCT同样可抑制腺泡细胞的脂质过氧化过程。
综上，应激状态下腺泡细胞的细胞命运倾向于规避多种形式的细胞死亡。xCT通过为谷胱甘肽池供能并维持活性氧平衡，特异性抑制腺泡细胞铁死亡。本研究数据表明，xCT可作为可药物靶向的关键调控节点，在应激条件下调控腺泡细胞的命运走向。
整体实验设计：将野生型（WT，Wild Type）或xCT基因敲除（KO，Knock Out）小鼠的新鲜分离胰腺腺泡细胞进行体外培养以诱导去分化，分别于第0天、第1天和第4天收集样本；每个时间点设置3个生物学重复。对不同基因型及不同时间点的RNA测序数据开展比较基因表达谱分析。