CPT2 inhibition enhances selective autophagy and proliferation in colorectal cancer via GPAT4-dependent glycerophospholipid biosynthesis

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