Liu Jingxin, Wu Chengyu, Lin Ziyun, Ma Maomao, Ma Wei, Yu Xuefeng, Wang Kai, Zeng Bin
College of Pharmacy, Shenzhen Technology University, Shenzhen, China.
Department of Biotechnology Research and Development, Guangzhou Dihe Biotechnology Co., Ltd, Guangzhou, China.
Front Immunol. 2025 Aug 29;16:1575242. doi: 10.3389/fimmu.2025.1575242. eCollection 2025.
Hepatic ischemia-reperfusion injury (HIRI) is a major complication in liver transplantation, hepatic surgeries, and shock-induced acute liver failure. This injury is characterized by mitochondrial dysfunction, oxidative stress, and calcium overload, with the mitochondrial permeability transition pore (mPTP) playing a pivotal role in mediating hepatocyte death. Cyclophilin D (CypD), a key regulator of mPTP opening, has long been associated with the exacerbation of HIRI. However, recent research has uncovered a protective aspect of CypD, revealing that it can regulate intermittent or "flickering" mPTP openings to control calcium overload, preserve mitochondrial integrity, and mitigate damage during ischemic stress. This review highlights the dual role of CypD in regulating mitochondrial damage through mPTP dynamics and its complex interplay with autophagy, specifically mitophagy, in liver injury. We also explore the emerging pharmacological and genetic approaches targeting PPIF, offering potential avenues for mitigating liver injury in clinical settings. This review integrates recent findings on PPIF's role in mPTP regulation, inflammation, autophagy, and mitophagy, proposing a nuanced view of its therapeutic potential in managing hepatic ischemia-reperfusion injury.
肝缺血再灌注损伤（HIRI）是肝移植、肝脏手术及休克诱发的急性肝衰竭中的主要并发症。这种损伤的特征为线粒体功能障碍、氧化应激和钙超载，线粒体通透性转换孔（mPTP）在介导肝细胞死亡中起关键作用。亲环素D（CypD）是mPTP开放的关键调节因子，长期以来一直被认为与HIRI的加重有关。然而，最近的研究发现了CypD的保护作用，表明它可以调节间歇性或“闪烁”的mPTP开放，以控制钙超载、维持线粒体完整性并减轻缺血应激期间的损伤。本综述强调了CypD在通过mPTP动态调节线粒体损伤及其在肝损伤中与自噬（特别是线粒体自噬）的复杂相互作用中的双重作用。我们还探讨了针对PPIF的新兴药理学和遗传学方法，为在临床环境中减轻肝损伤提供了潜在途径。本综述整合了关于PPIF在mPTP调节、炎症、自噬和线粒体自噬中作用的最新发现，提出了其在治疗肝缺血再灌注损伤中治疗潜力的细微观点。
