CPT2 inhibition activates selective autophagy by enhancing glycerophospholipid biosynthesis in colorectal cancer

Metabolic reprogramming is one of the hallmark events in colorectal cancer (CRC).  Tumor cells adapt to microenvironmental changes by regulating energy and biomaterial metabolism. This study identified abnormal lipid accumulation and significant downregulation of fatty acid metabolism in CRC. The core gene of this pathway, CPT2, critically impacts CRC patient survival and regulates tumor cell proliferation both in vitro and in vivo. Metabolite analysis demonstrated that CPT2 knockdown induced accumulation of glycerophospholipids (GPs), primarily phosphatidylcholine (PC) and phosphatidylethanolamine (PE), driven by enhanced long-chain fatty acid (LCFA)-dependent GP biosynthesis mediated by GPAT4. Transcriptomic analysis and subsequent experiments revealed that GP accumulation, as key components of vesicles and autophagosomes, promoted autophagosome maturation and elongation, thereby activating selective autophagy (lipophagy) in CRC cells and accelerating tumor progression. These findings enhance understanding of tumor metabolic characteristics and identify novel diagnostic and therapeutic targets for CRC.