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Abstract：
BACKGROUND: Ferroptosis is a newly recognized form of regulatory cell death characterized by severe lipid peroxidation triggered by iron overload and the production of reactive oxygen species (ROS). However, the role of ferroptosis in severe acute pancreatitis(SAP) has not been fully elucidated.
METHODS: We established four severe acute pancreatitis models of rats including the sham control group, the SAP group, the Fer -1-treated SAP (SAP + Fer-1) group, the 3-MA-treated SAP (SAP + 3-MA) group. The SAP group was induced by retrograde injection of sodium taurocholate into the pancreatic duct. The other two groups were intraperitoneally injected with ferroptosis inhibitor (Fer-1) and autophagy inhibitor (3-MA), respectively. The model of severe acute pancreatitis with amylase crest-related inflammatory factors was successfully established. Then we detected ferroptosis (GPX4, SLC7A1 etc.) and autophagy-related factors (LC3II, p62 ect.) to further clarify the relationship between ferroptosis and autophagy.
RESULTS: Our study found that ferroptosis occurs during the development of SAP, such as iron and lipid peroxidation in pancreatic tissues, decreased levels of reduced glutathione peroxidase 4 (GPX 4) and glutathione (GSH), and increased malondialdehyde(MDA) and significant mitochondrial damage. In addition, ferroptosis related proteins such as GPX4, solute carrier family 7 member 11(SLC7A11) and ferritin heavy chain 1(FTH1) were significantly decreased. Next, the pathogenesis of ferroptosis in SAP was studied. First, treatment with the ferroptosis inhibitor ferrostatin-1(Fer-1) significantly alleviated ferroptosis in SAP. Interestingly, autophagy occurs during the pathogenesis of SAP, and autophagy promotes the occurrence of ferroptosis in SAP. Moreover, 3-methyladenine (3-MA) inhibition of autophagy can significantly reduce iron overload and ferroptosis in SAP.
CONCLUSIONS: Our results suggest that ferroptosis is a novel pathogenesis of SAP and is dependent on autophagy. This study provides a new theoretical basis for the study of SAP.
METHODS: We established four severe acute pancreatitis models of rats including the sham control group, the SAP group, the Fer -1-treated SAP (SAP + Fer-1) group, the 3-MA-treated SAP (SAP + 3-MA) group. The SAP group was induced by retrograde injection of sodium taurocholate into the pancreatic duct. The other two groups were intraperitoneally injected with ferroptosis inhibitor (Fer-1) and autophagy inhibitor (3-MA), respectively. The model of severe acute pancreatitis with amylase crest-related inflammatory factors was successfully established. Then we detected ferroptosis (GPX4, SLC7A1 etc.) and autophagy-related factors (LC3II, p62 ect.) to further clarify the relationship between ferroptosis and autophagy.
RESULTS: Our study found that ferroptosis occurs during the development of SAP, such as iron and lipid peroxidation in pancreatic tissues, decreased levels of reduced glutathione peroxidase 4 (GPX 4) and glutathione (GSH), and increased malondialdehyde(MDA) and significant mitochondrial damage. In addition, ferroptosis related proteins such as GPX4, solute carrier family 7 member 11(SLC7A11) and ferritin heavy chain 1(FTH1) were significantly decreased. Next, the pathogenesis of ferroptosis in SAP was studied. First, treatment with the ferroptosis inhibitor ferrostatin-1(Fer-1) significantly alleviated ferroptosis in SAP. Interestingly, autophagy occurs during the pathogenesis of SAP, and autophagy promotes the occurrence of ferroptosis in SAP. Moreover, 3-methyladenine (3-MA) inhibition of autophagy can significantly reduce iron overload and ferroptosis in SAP.
CONCLUSIONS: Our results suggest that ferroptosis is a novel pathogenesis of SAP and is dependent on autophagy. This study provides a new theoretical basis for the study of SAP.
摘要：
背景：Ferroptosis是一种新认识的调节性细胞死亡形式，其特征在于由铁超负荷和活性氧（ROS）的产生引发的严重脂质过氧化。然而,严重急性胰腺炎(SAP)中铁死亡的作用尚未完全阐明.
方法：我们建立了4个大鼠重症急性胰腺炎模型，包括假对照组，SAP集团，Fer-1处理的SAP（SAP+Fer-1）组，3-MA处理的SAP(SAP+3-MA)组。SAP组采用胰管逆行注射牛磺胆酸钠诱导。其他两组均腹腔注射铁凋亡抑制剂(Fer-1)和自噬抑制剂(3-MA),分别。成功建立了淀粉酶相关炎症因子的重症急性胰腺炎模型。然后我们检测到铁凋亡（GPX4，SLC7A1等。)和自噬相关因子(LC3II，p62ect.)进一步阐明铁凋亡与自噬的关系。
结果：我们的研究发现，在SAP的发展过程中会发生铁死亡，例如胰腺组织中的铁和脂质过氧化，还原型谷胱甘肽过氧化物酶4（GPX4）和谷胱甘肽（GSH）的水平降低，并增加丙二醛(MDA)和显著的线粒体损伤。此外,铁凋亡相关蛋白如GPX4、溶质载体家族7成员11(SLC7A11)和铁蛋白重链1(FTH1)均显著降低。接下来,研究了SAP中铁死亡的发病机制。首先,用铁凋亡抑制剂铁抑素-1（Fer-1）治疗可显着减轻SAP的铁凋亡。有趣的是,自噬发生在SAP的发病机制中，自噬促进SAP铁凋亡的发生。此外，3-甲基腺嘌呤（3-MA）抑制自噬可以显着降低SAP中铁过载和铁凋亡。
结论：我们的结果表明，铁凋亡是SAP的一种新的发病机制，并且依赖于自噬。本研究为SAP的研究提供了新的理论基础。
方法：我们建立了4个大鼠重症急性胰腺炎模型，包括假对照组，SAP集团，Fer-1处理的SAP（SAP+Fer-1）组，3-MA处理的SAP(SAP+3-MA)组。SAP组采用胰管逆行注射牛磺胆酸钠诱导。其他两组均腹腔注射铁凋亡抑制剂(Fer-1)和自噬抑制剂(3-MA),分别。成功建立了淀粉酶相关炎症因子的重症急性胰腺炎模型。然后我们检测到铁凋亡（GPX4，SLC7A1等。)和自噬相关因子(LC3II，p62ect.)进一步阐明铁凋亡与自噬的关系。
结果：我们的研究发现，在SAP的发展过程中会发生铁死亡，例如胰腺组织中的铁和脂质过氧化，还原型谷胱甘肽过氧化物酶4（GPX4）和谷胱甘肽（GSH）的水平降低，并增加丙二醛(MDA)和显著的线粒体损伤。此外,铁凋亡相关蛋白如GPX4、溶质载体家族7成员11(SLC7A11)和铁蛋白重链1(FTH1)均显著降低。接下来,研究了SAP中铁死亡的发病机制。首先,用铁凋亡抑制剂铁抑素-1（Fer-1）治疗可显着减轻SAP的铁凋亡。有趣的是,自噬发生在SAP的发病机制中，自噬促进SAP铁凋亡的发生。此外，3-甲基腺嘌呤（3-MA）抑制自噬可以显着降低SAP中铁过载和铁凋亡。
结论：我们的结果表明，铁凋亡是SAP的一种新的发病机制，并且依赖于自噬。本研究为SAP的研究提供了新的理论基础。
