Abstract：
Hepatic ischemia-reperfusion injury (IRI) is a major cause of liver damage during hepatic resection, transplantation, and other surgical procedures, often leading to graft failure and liver dysfunction. Recent studies have identified ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, as a key contributor to IRI. In this study, we investigated the protective effects of Ticlopidine, a thienopyridine compound and platelet aggregation inhibitor, on hepatic IRI. Using a C57BL/6J mouse model, we demonstrated that prophylactic Ticlopidine treatment significantly reduced necrotic and fibrotic areas in liver tissues, as well as serum levels of alanine transaminase (ALT) and aspartate aminotransferase (AST). Prussian Blue staining revealed that Ticlopidine pretreatment decreased iron accumulation in hepatic tissues, whereas markers of lipid peroxidation (malondialdehyde and 4-hydroxynonenal) and ferroptosis (PTGS2) were significantly downregulated. Additionally, Ticlopidine ameliorated inflammatory infiltration as indicated by reduced Gr-1 staining. In vitro, Ticlopidine dose-dependently inhibited ferroptosis induced by various inducers in liver cancer cell lines HUH7 and fibrosarcoma cells HT1080. The protective effects involved partial rescue of lipid peroxidation, significant reduction of ferrous iron levels, and strong protection against mitochondrial damage. These findings suggested that Ticlopidine acts as a broad-spectrum ferroptosis inhibitor, offering a promising therapeutic approach for protecting the liver against IRI.
摘要：
肝缺血再灌注损伤(IRI)是肝切除术中肝损伤的主要原因,移植,和其他外科手术,常导致移植物衰竭和肝功能障碍。最近的研究已经确定了铁死亡，一种以铁依赖性脂质过氧化为特征的调节性细胞死亡形式，作为IRI的关键贡献者。在这项研究中,我们研究了噻氯匹定的保护作用，噻吩并吡啶化合物和血小板聚集抑制剂，肝IRI。使用C57BL/6J小鼠模型,我们证明预防性噻氯匹定治疗可显着减少肝组织中的坏死和纤维化区域，以及丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）的血清水平。普鲁士蓝染色显示噻氯匹定预处理减少肝组织中铁的积累，而脂质过氧化（丙二醛和4-羟基壬烯醛）和铁凋亡（PTGS2）的标志物显着下调。此外,噻氯匹定改善了炎症浸润,如Gr-1染色减少所示。体外，噻氯匹定剂量依赖性地抑制各种诱导剂在肝癌细胞系HUH7和纤维肉瘤细胞HT1080中诱导的铁凋亡。保护作用涉及脂质过氧化的部分挽救，亚铁含量显著降低，以及对线粒体损伤的强大保护。这些发现表明噻氯匹定是一种广谱的铁凋亡抑制剂，提供了一种有前途的治疗方法来保护肝脏免受IRI。
