Endothelial F3-mediated autolysosome and lipid metabolism promote resistance to anti-VEGFA therapy in metastatic colorectal cancer

作者：Nan Huang, Nan Huang, Junxi Ren, Xinyue Deng, Qiyu Bao, Genjie Huang, Shimeng Zhi, Yuedan Li, Juan Li, Binghui Hu, Dongqiang Zeng, Huiying Sun, Wei Zeng, Min Shi, Wangjun Liao, Jianhua Wu, Na Huang, Na Huang · 发表于：Autophagy · 年份：2025 · DOI：10.1080/15548627.2025.2551720 · 被引用次数：4 · 研究领域：Cancer, Lipids, and Metabolism、Lipid metabolism and disorders、Cancer, Hypoxia, and Metabolism

Patients with metastatic colorectal cancer (mCRC) to the liver exhibit poor survival rates. Chemotherapy combined with anti-vascular therapy has emerged as the standard treatment, but resistance to anti-VEGFA therapy inevitably develops. The metabolic reprogramming of tumor vascular endothelial cells (TECs) plays a crucial, yet still poorly understood, role in the development of therapeutic resistance. We identified lipid-rich and fatty acid oxidation (FAO)-activated proliferating TECs in fatty colorectal cancer liver metastasis (CRLM) that mediate resistance to anti-VEGFA treatment. The TEC-specific F3 protein inhibited the macroautophagy/autophagy-lysosome pathway through the MAPK/JNK-MAPK/ERK-TP53/p53 signaling axis, thereby prevented CPT1A protein degradation and enhanced FAO. F3 was also involved in promoting lipid uptake and lipophagy. This process promoted cellular FAO under conditions of fatty acids and anti-VEGFA stimulation. Targeting FAO proved effective in overcoming resistance to anti-VEGFA treatment. Our findings elucidated the role of lipid metabolism in therapy-resistant TECs in fatty CRLM and provided a theoretical foundation for further research on anti-VEGFA therapy resistance. Moreover, we underscored the potential of combining FAO inhibitors to enhance the efficacy of anti-angiogenic therapy.