Regulatory role of phosphatidylcholine metabolic reprogramming in colorectal cancer progression and neutrophil interactions

Colorectal cancer (CRC) remains a significant global health challenge due to its high incidence, mortality, and persistent issues with drug resistance, recurrence, and metastasis. Lipid metabolism reprogramming-a hallmark of CRC-plays a critical role in tumor progression. Mendelian randomization analysis established a causal relationship between phosphatidylcholine (PC) metabolism and CRC. Integrative analyses of transcriptomic and lipidomic data demonstrated that elevated PC levels are linked to enhanced CRC proliferation, metastasis, drug resistance, and increased tumor-associated neutrophils (TANs) infiltration. Machine-learning-based diagnostic and prognostic models underscore the clinical significance of PC-metabolism-related genes, identifying <i>ATP10A</i> and <i>DBI</i> as central dysregulated genes. <i>ATP10A</i>, markedly overexpressed in CRC, drives tumor growth, metastasis, and chemoresistance by upregulating TAN-related chemokines and <i>TGF-β</i>, whereas <i>DBI</i> appears protective. Collectively, these findings define PC metabolism as a potential therapeutic target and provide insight for developing combination strategies to mitigate CRC progression and improve outcomes.