Cisplatin-induced disruption of mitochondrial divisome leads to enhanced cisplatin resistance in cholangiocarcinoma

作者：Guoyue Lv, Wentao Mu, Yannan Cao, Xiaodong Sun, Wei Feng, Kaiyuan Chai, Bo Huang, Jianpeng Zhou, Chuanlei Wang, Mingyue Li, Xiaohong Du, Wei Qiu, Meng Wang, Xiaoju Shi, Jun-Feng Ye, Xing-Kai Liu, Heyu Huang, Yuguo Chen, Zhao-Ming Gou, Ping Zhang, Yahui Liu, Guangyi Wang, Zhongqi Fan · 发表于：Journal of Hepatology · 年份：2025 · DOI：10.1016/j.jhep.2025.03.028 · 被引用次数：16 · 研究领域：Mitochondrial Function and Pathology、Cholangiocarcinoma and Gallbladder Cancer Studies、Cancer, Hypoxia, and Metabolism

BACKGROUND & AIMS: Cisplatin (CDDP)-based chemotherapy is the primary treatment for advanced cholangiocarcinoma (CCA), but its clinical efficacy is limited. The mitochondrial divisome (MD) is crucial for regulating mitochondrial division, but its roles in CDDP resistance remain unclear. METHODS: Alternations of mitochondrial morphology, expression levels and localization of MD components in CCA under CDDP treatment were evaluated using fluorescence labeling and mitochondrial isolation at cellular and organoid levels. Gene editing and other strategies demonstrated the link between mitochondrial hyperfusion and CDDP resistance. RNA sequencing revealed altered molecular landscapes in CCA cells following CDDP exposure. Mass spectrometry and immunoprecipitation were mainly adopted to explore the mechanisms of degradation of the actin-binding protein INF2 (inverted formin-2). Endoplasmic reticulum (ER)-phagy was characterized using stable transfection of ssRFP-GFP-KDEL. The clinical significance of INF2 was assessed by analyzing tumor samples of 438 patients with CCA using tissue microarray. Combination therapy efficacy was validated in cell line- and patient-derived xenograft mouse models. RESULTS: CDDP dramatically damaged various MD components, leading to increased F-actin peripheral polymerization, decreased ER colocalization with mitochondria, and INF2 degradation. These events promoted adaptive mitochondrial hyperfusion, contributing to CDDP resistance in CCA. INF2 plays a pi...