Journal Article

MTFR2‐Mediated Fission Drives Fatty Acid and Mitochondrial Co‐Transfer from Hepatic Stellate Cells to Tumor Cells Fueling Oncogenesis

Zhou, Baoyong, Huang, Zuotian, Yang, Jun, Wu, Zhongjun, Liu, Qiang, Jiang, Ning, Luo, Jing, Ren, Cong, Li, Zhenghang, Zhang, La

2025

Overview

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. In the tumor margin of hepatocellular carcinoma (HCC), activated hepatic stellate cells upregulate MTFR2, initiating inhibiting DRP1 degradation and mitochondrial fission. This enhances mitochondrial availability and facilitates FAs synthesis via ACC1. Additionally, fission promotes RAC1‐mediated cytoskeletal remodeling and Miro1‐mediated mitochondrial transport, enabling HCC cells to utilize transferred resources for increased fatty acid oxidation and ATP production.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Animals / Apoptosis / Carcinogenesis - genetics / Carcinogenesis - metabolism / Carcinoma, Hepatocellular - genetics / Carcinoma, Hepatocellular - metabolism / Carcinoma, Hepatocellular - pathology / Cell growth / Cell Line, Tumor / DNA damage / Dynamins - metabolism / Extracellular matrix / fatty acid transfer / Fatty acids / Fatty Acids - metabolism / Genes / hepatic stellate cell / Hepatic Stellate Cells - metabolism / hepatocellular carcinoma / Humans / Liver cancer / Liver Neoplasms - genetics / Liver Neoplasms - metabolism / Liver Neoplasms - pathology / Metabolism / Mice / Microscopy / Mitochondria / Mitochondria - metabolism / mitochondrial dynamics / Mitochondrial Dynamics - genetics / Mitochondrial Dynamics - physiology / Mitochondrial Proteins - genetics / Mitochondrial Proteins - metabolism / mitochondrial transfer / Oxidation / Oxidative stress / Respiration