Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400030, China.
Department of Obstetrics and Gynecology, Chongqing Health Center for Women and Children (Women and Children's Hospital of Chongqing Medical University), Chongqing, 401120, China.
Biochem Biophys Res Commun. 2024 Nov 12;733:150436. doi: 10.1016/j.bbrc.2024.150436. Epub 2024 Jul 23.
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.
肝缺血再灌注损伤（IRI）是肝切除、移植和其他手术过程中肝脏损伤的主要原因，常导致移植物衰竭和肝功能障碍。最近的研究表明，铁死亡作为一种受调控的细胞死亡形式，其特征是铁依赖性脂质过氧化，是 IRI 的一个关键因素。在本研究中，我们研究了噻氯匹定（一种噻吩并吡啶化合物和血小板聚集抑制剂）对肝 IRI 的保护作用。使用 C57BL/6J 小鼠模型，我们证明预防性噻氯匹定治疗可显著减少肝组织的坏死和纤维化区域，以及血清丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）水平。普鲁士蓝染色显示，噻氯匹定预处理可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）和铁死亡（PTGS2）的标志物则明显下调。此外，噻氯匹定减轻了炎症浸润，Gr-1 染色减少。在体外，噻氯匹定剂量依赖性地抑制肝癌细胞系 HUH7 和纤维肉瘤细胞 HT1080 中各种诱导剂引起的铁死亡。保护作用涉及对脂质过氧化的部分挽救、亚铁水平的显著降低以及对线粒体损伤的强烈保护。这些发现表明，噻氯匹定作为一种广谱铁死亡抑制剂，为保护肝脏免受 IRI 提供了一种有前途的治疗方法。
