Role of TRAIL in mediating the effect of lipidome on breast cancer: a Mendelian randomization study

Breast cancer (BC) is the most common malignancy in women and remains a major cause of cancer-related death. Growing observational and multi-omics evidence suggests that dysregulated lipid metabolism and alterations in circulating lipidomes are involved in BC development, yet their causal relationships and underlying mechanisms remain unclear. This study aimed to elucidate the causal effect of lipidomes on BC, as well as its possible mechanism of action, and to investigate the mediating effect of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on the risk of BC.

Two-sample Mendelian randomization (MR) was used to analyze genome-wide association study (GWAS) data on 179 lipidomes-related single nucleotide polymorphisms (SNPs) and BC (15,680 cases, 167,189 controls) to identify potential mediators. MR-Egger regression, Cochran's Q, MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and leave-one-out analysis ensured result robustness. Molecular docking was performed using AutoDock to model TRAIL-death receptor 4 (DR4) interactions with lipidomes. Foldseek homology search analyzed structural similarities, and molecular dynamics simulations identified key binding residues and interaction stability.

This modelling results revealed that in the 179 lipidomes, a notable positive causal relationship was found between phosphatidylcholine (16:0_16:0) and BC risk [P=0.02, odds ratio (OR) =1.0764, 95% confidence interval (CI): 1.0124-1.1443], as well as a causal association between phosphatidylcholine (16:0_16:0) and TRAIL (P=0.02, OR =0.9219, 95% CI: 0.8588-0.9896), along with a negative causal association between TRAIL and BC (P=0.02, OR =0.9504, 95% CI: 0.9110-0.9916). Sensitivity analysis revealed no significant heterogeneity. According to structural homology searches, the molecular recognition between TRAIL and DR4 exhibited evolutionary structural conservation. The binding of phosphatidylcholine significantly weakened the hydrogen bonds, van der Waals interactions, and binding free energy between TRAIL and DR4, thereby disrupting the TRAIL-mediated apoptotic signaling pathway in BC cells.

MR implicates PC (16:0_16:0) in BC risk with TRAIL as a putative mediator, nominating PC (16:0_16:0) for biomarker development and the lipid-TRAIL pathway as a potential therapeutic avenue. Translation will require replication and prospective validation, especially beyond European ancestry.