Single-cell transcriptomics and Mendelian randomization reveal LUCAT1's role in right-sided colorectal cancer risk.

Colorectal cancer (CRC) is a malignancy with high incidence and mortality rates globally, categorized into left-sided and right-sided CRC, each exhibiting significant differences in molecular characteristics, clinical manifestations, and prognosis. This study employed single-cell transcriptomic data and various bioinformatics approaches, such as two-sample Mendelian randomization, reverse Mendelian randomization, colocalization analysis, directed filtering, pseudotime analysis, and intercellular communication analysis. It analyzed cellular-level disparities between left-sided and right-sided CRC, identifying distinct subpopulations with characteristic variations. For these cells, two-sample Mendelian randomization was utilized to explore gene-to-one-sided CRC causality. LUCAT1 was enriched in high-abundance monocyte subpopulations in right-sided CRC and demonstrated potential risk factor status through Mendelian randomization analysis. The specific single-nucleotide polymorphism (SNP) rs10774624 was associated with an increased risk of CRC. Moreover, metabolic pathway analysis revealed that LUCAT1 monocytes exhibit lower communication activity in the tumor microenvironment and heightened activity in metabolic functions like glycosaminoglycan degradation. Its biological functions are related to the positive regulation of interleukin-6 production and NF-kappa B signaling, among others. This study confirmed a potential causal relationship between LUCAT1 and right-sided CRC risk through Mendelian randomization analysis. These findings provide novel insights into the pathogenesis of right-sided CRC and may aid in developing early detection and treatment strategies for right-sided CRC.