Deng Peng, Wu You, Wan Li, Sun Xiangfu, Sun Quanchao
Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Biomedicines. 2025 Jun 30;13(7):1594. doi: 10.3390/biomedicines13071594.
: Lung ischemia reperfusion injury (LIRI) is a severe complication after lung transplantation (LT). Ferroptosis contributes to the pathogenesis of LIRI. Maresin1 (MaR1) is an endogenous pro-resolving lipid mediator that exerts protective effects against multiorgan diseases. However, the role and mechanism of MaR1 in the ferroptosis of LIRI after LT need to be further investigated. : A mouse LT model and a pulmonary vascular endothelial cell line after hypoxia reoxygenation (H/R) culture were established in our study. Histological morphology and inflammatory cytokine levels predicted the severity of LIRI. Cell viability and cell injury were determined by CCK-8 and LDH assays. Ferroptosis biomarkers, including Fe, MDA, 4-HNE, and GSH, were assessed by relevant assay kits. Transferrin receptor (TFRC) and Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) protein levels were examined by western blotting. In vitro, lipid peroxide levels were detected by DCFH-DA staining and flow cytometry analysis. The ultrastructure of mitochondria was imaged using transmission electron microscopy. Furthermore, the potential mechanism by which MaR1 regulates ferroptosis was explored and verified with signaling pathway inhibitors using Western blotting. : MaR1 protected mice from LIRI after LTx, which was reversed by the ferroptosis agonist Sorafenib in vivo. MaR1 administration decreased Fe, MDA, 4-HNE, TFRC, and ACSL4 contents, increased GSH levels, and ameliorated mitochondrial ultrastructural injury after LTx. In vitro, Sorafenib resulted in lower cell viability and worsened cell injury and enhanced the hallmarks of ferroptosis after H/R culture, which was rescued by MaR1 treatment. Mechanistically, the protein kinase A and YAP inhibitors partly blocked the effects of MaR1 on ferroptosis inhibition and LIRI protection. : This study revealed that MaR1 alleviates LIRI and represses ischemia reperfusion-induced ferroptosis via the PKA-Hippo-YAP signaling pathway, which may offer a promising theoretical basis for the clinical application of organ protection after LTx.
肺缺血再灌注损伤（LIRI）是肺移植（LT）后的一种严重并发症。铁死亡参与了LIRI的发病机制。maresin1（MaR1）是一种内源性促消退脂质介质，对多器官疾病具有保护作用。然而，MaR1在LT后LIRI铁死亡中的作用和机制尚需进一步研究。：本研究建立了小鼠LT模型和缺氧复氧（H/R）培养后的肺血管内皮细胞系。组织学形态和炎性细胞因子水平可预测LIRI的严重程度。通过CCK-8和LDH检测确定细胞活力和细胞损伤。通过相关检测试剂盒评估铁死亡生物标志物，包括铁、丙二醛（MDA）、4-羟基壬烯醛（4-HNE）和谷胱甘肽（GSH）。通过蛋白质印迹法检测转铁蛋白受体（TFRC）和酰基辅酶A合成酶长链家族成员4（ACSL4）的蛋白水平。在体外，通过2',7'-二氯二氢荧光素二乙酸酯（DCFH-DA）染色和流式细胞术分析检测脂质过氧化物水平。使用透射电子显微镜对线粒体超微结构进行成像。此外，利用信号通路抑制剂通过蛋白质印迹法探索并验证了MaR1调节铁死亡的潜在机制。：MaR1可保护小鼠免受LTx后的LIRI影响，而铁死亡激动剂索拉非尼在体内可逆转这一作用。给予MaR1可降低LTx后铁、MDA、4-HNE、TFRC和ACSL4的含量，提高GSH水平，并改善线粒体超微结构损伤。在体外，索拉非尼导致细胞活力降低、细胞损伤加重，并增强了H/R培养后铁死亡的特征，而MaR1处理可挽救这些变化。机制上，蛋白激酶A和Yes相关蛋白（YAP）抑制剂部分阻断了MaR1对铁死亡抑制和LIRI保护的作用。：本研究表明，MaR1通过蛋白激酶A-河马-YAP信号通路减轻LIRI并抑制缺血再灌注诱导的铁死亡，这可能为LTx后器官保护的临床应用提供有前景的理论基础。
