我们近期报道自噬和脂肪分解代谢保护肝癌细胞免于葡萄糖饥饿引起的死亡(Hepatology 2015)。前期临床肝癌队列研究发现糖尿病合并肝癌患者的存活期更长，尤其经肝动脉栓塞术治疗的差别更明显。实验发现糖尿病药物二甲双胍促进葡萄糖饥饿导致的肝癌细胞死亡，但栓塞化疗药阿霉素则保护细胞。机制研究发现线粒体自噬保护葡萄糖饥饿导致的细胞死亡，但对二甲双胍联合葡萄糖饥饿所致死亡无效。因而得出研究假设：1）肝癌线粒体自噬的保护作用依赖于线粒体能量代谢；2）二甲双胍联合肝动脉结扎可有效治疗肝癌。计划研究：1）肝癌细胞Parkin依赖或非依赖线粒体自噬的分子机制；2）线粒体能量代谢对线粒体自噬和细胞死亡的影响；3）采用人源肝癌（PDX）和细胞株的小鼠原位移植瘤模型，验证二甲双胍联合肝动脉结扎对肝癌移植瘤坏死、复发和小鼠长期存活的治疗作用。预期结果将阐明肝癌细胞线粒体自噬通路，并建立更有效肝癌联合治疗方法。

We recently reported that autophagy and lipid catabolism protected hepatocellular carcinoma (HCC) cells from glucose starvation induced cell death (Hepatology 2015). The preliminary study based on a clinical HCC patient cohort showed that diabetic HCC patients had longer survival, especially after transarterial embolization treatment. Accordingly, anti-diabetic drug metformin sensitized glucose starvation induced cell death, but chemotherapeutic drug doxorubicin protected. The preliminary mechanical study found that mitophagy could protect HCC cells from glucose starvation induced cell death, but it failed in the combined treatment of glucose starvation and metformin. Thus, we proposed the below hypothesis: 1) mitophagy may be dependent on mitochondrial energy metabolism; 2) the combined treatment of metformin and transarterial ligation may be useful for HCC treatment. We plan to do the following investigations: 1) to study the molecular mechanisms involved in parkin-dependent or -independent mitophagy; 2) to determine the effect of mitochondrial energy metabolism on mitophagy and cell death; 3) to validate the therapeutic effect of combined treatment with metformin and transarterial ligation on HCC tumor cell death, recurrence and mice long-term survival by using mice orthotopic xenograft models of HCC cell lines and patient-derived xenograft. The results to be obtained will help clarify the molecular pathways of mitophagy in HCC, and establish better regional combined therapy against HCC.