Transarterial embolization/transarterial chemoembolization (TAE/TACE) is the acceptable palliative treatment for hepatocellular carcinoma (HCC), mainly through ischemic necrosis induced by arterial embolization. However, how HCC cells survive under such ischemic hypoxic condition remains unclear, which can be exploited to potentiate TAE/TACE treatment. We hypothesized that targeting mitophagy can increase HCC cell apoptosis during hypoxia. HCC cells were subjected to hypoxia and then mitophagy was quantified. The role of dynamin-related protein 1 (DRP1) in hypoxia-induced HCC mitophagy was determined. Moreover, the synergistic effect of hypoxia and DRP1 inhibitor on HCC apoptosis was assessed in vitro and in vivo. Clinical association between DRP1 expression and outcome for HCC patients was validated. HCC cells that survived hypoxia showed significantly increased DRP1-mediated mitochondrial fission and mitophagy compared with cells in normoxia. Hypoxia induced mitophagy in surviving HCC cells by enhancing DRP1 expression and its translocation into the mitochondria and excessive mitochondrial fission into fragments. Blocking the DRP1 heightened the possibility of hypoxic cytotoxicity to HCC cells due to impaired mitophagy and increased the mitochondrial apoptosis, which involved decreased in mitochondrial membrane potential and mitochondrial release of apoptosis-inducing factor and cytochrome c. Additionally, DRP1 inhibitor Mdivi-1 suppressed the in vivo growth of hypoxia-exposed HCC cells. High expression of DRP1 was significantly associated with shorter survival in HCC patients. In conclusion, our results demonstrate that blocking DRP1-mediated mitochondrial fission and mitophagy increases the incidence of mitochondrial apoptosis of HCC cells during hypoxia, suggesting the new approach of targeting mitophagy to potentiate TAE/TACE.

经动脉栓塞/经动脉化学栓塞（TAE / TACE）是肝细胞癌（HCC）的可接受的姑息治疗，主要是通过动脉栓塞引起的缺血性坏死。然而，尚不清楚HCC细胞在这种缺血性缺氧条件下如何生存，可用于增强TAE / TACE治疗。我们假设靶向线粒体可以在缺氧期间增加HCC细胞凋亡。使HCC细胞缺氧，然后量化线粒体。确定了dynamin相关蛋白1（DRP1）在缺氧诱导的HCC线粒体吞噬中的作用。此外，在体外和体内评估了缺氧和DRP1抑制剂对HCC凋亡的协同作用。验证了DRP1表达与HCC患者预后之间的临床关联。与低氧细胞相比，在低氧条件下存活的HCC细胞显示DRP1介导的线粒体裂变和线粒体显着增加。缺氧通过增强DRP1的表达及其易位到线粒体中和过度的线粒体分裂为碎片，从而在存活的HCC细胞中诱导线粒体吞噬。阻断DRP1会增加由于线粒体受损而导致HCC细胞发生低氧细胞毒性的可能性，并增加线粒体的细胞凋亡，这涉及线粒体膜电位的降低以及线粒体细胞凋亡诱导因子和细胞色素c的释放。此外，DRP1抑制剂Mdivi-1抑制了缺氧暴露的HCC细胞的体内生长。DRP1的高表达与肝癌患者的生存期短显着相关。结论，