Zhang La, Zhou Baoyong, Yang Jun, Ren Cong, Luo Jing, Li Zhenghang, Liu Qiang, Huang Zuotian, Wu Zhongjun, Jiang Ning
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, College of Basic Medical Sciences of Chongqing Medical University, Chongqing, 400016, China.
Department of Pathology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China.
Adv Sci (Weinh). 2025 Jun;12(23):e2416419. doi: 10.1002/advs.202416419. Epub 2025 May 14.
The tumor margin of hepatocellular carcinoma (HCC) is a critical zone where cancer cells invade the surrounding stroma, exhibiting unique and more invasive metabolic and migratory features compared to the tumor center, driving tumor expansion beyond the primary lesion. Studies have shown that at this critical interface, HCC cells primarily rely on fatty acid oxidation to meet their energy demands, although the underlying mechanisms remain unclear. This study demonstrates that activated hepatic stellate cells (HSCs) at the tumor margin play a pivotal role in sustaining the metabolic needs of HCC cells. Specifically, it is discovered that mitochondrial fission regulator 2 (MTFR2) in HSCs interacts with dynamin-related protein 1 (DRP1, a known mitochondrial fission machinery), preventing its lysosomal degradation, which in turn promotes mitochondrial fission. This MTFR2-driven mitochondrial fission enhances the transfer of both fatty acids and mitochondria to HCC cells, supplying essential metabolic substrates and reinforcing the mitochondrial machinery critical for tumor growth. The findings suggest that targeting MTFR2-driven mitochondrial fission may offer a novel therapeutic avenue for interfering with the metabolic crosstalk between tumor cells and the stromal niche.
肝细胞癌（HCC）的肿瘤边缘是一个关键区域，癌细胞在此侵入周围基质，与肿瘤中心相比，表现出独特且更具侵袭性的代谢和迁移特征，促使肿瘤扩展至原发灶之外。研究表明，在这个关键界面，HCC细胞主要依靠脂肪酸氧化来满足其能量需求，尽管其潜在机制尚不清楚。本研究表明，肿瘤边缘活化的肝星状细胞（HSCs）在维持HCC细胞的代谢需求方面起关键作用。具体而言，研究发现HSCs中的线粒体裂变调节因子2（MTFR2）与动力相关蛋白1（DRP1，一种已知的线粒体裂变机制）相互作用，阻止其溶酶体降解，进而促进线粒体裂变。这种由MTFR2驱动的线粒体裂变增强了脂肪酸和线粒体向HCC细胞的转移，提供了必需的代谢底物，并加强了对肿瘤生长至关重要的线粒体机制。这些发现表明，靶向MTFR2驱动的线粒体裂变可能为干扰肿瘤细胞与基质微环境之间的代谢串扰提供一条新的治疗途径。
