Abstract
BACKGROUND: This exploratory, hypothesis-generating study aimed to evaluate the potential genetically informed association between CD300C gene expression and lung adenocarcinoma (LUAD) risk, and to investigate the possible mediating role of CD62L⁻ monocytes using a multi-omics Mendelian randomization (MR) framework. METHODS: We integrated LUAD GWAS summary statistics, peripheral blood eQTL and pQTL data, and transcriptomic profiles. Candidate genes were prioritized by overlapping evidence from eQTL-MR, pQTL-MR, and expression analyses. A three-step Mendelian randomization model estimated the total, mediated, and direct effects of CD300C expression on LUAD risk via CD62L⁻ monocytes. RESULTS: CD300C was the only gene consistently associated with LUAD across all omics stages. Higher CD300C expression was associated with reduced LUAD risk (β = − 0.030, OR = 0.97, 95% CI: 0.942–0.999), while the proportion of CD62L⁻ monocytes was also inversely associated with LUAD (β = − 0.086, OR = 0.91, 95% CI: 0.855–0.982). CD300C expression was positively associated with CD62L⁻ monocytes (β = 0.008, OR = 1.082, 95% CI: 1.029–1.139). The estimated mediated effect was β = -0.007, accounting for 22.92% of the total association. CONCLUSIONS: Our findings provide preliminary, genetically informed evidence that higher CD300C expression may be nominally associated with reduced LUAD risk, potentially in part through CD62L⁻ monocytes. Given the limited statistical power and the lack of significance after multiple-testing correction, these findings should be interpreted as exploratory and hypothesis-generating. They nominate the CD300C–CD62L⁻ monocyte axis as a hypothesis for future investigation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12672-026-04481-8.