Genetic Insight Into Dissecting the <scp>FODMAP</scp> Diet Frame and Liver Cancer: The Mediation Role of Efferocytosis and Trogocytosis

The etiology of liver cancer remains poorly understood, particularly regarding its potential association with dietary patterns rich in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP). This study investigated the genetic relationships between FODMAP-related dietary intake and liver cancer risk and further assessed whether proteins involved in efferocytosis and trogocytosis mediate these associations. This study applied two-sample Mendelian randomization (MR) and mediation MR analyses to examine the links among FODMAP-related dietary factors, trogocytosis, efferocytosis, and liver cancer. Summary statistics were obtained from MVP-GWAS for liver cancer, deCODE for trogocytosis and efferocytosis, and the UK Biobank for FODMAP dietary traits. A two-step mediation MR analysis was then performed to determine whether the pathways of efferocytosis and trogocytosis mediated the genetic associations between FODMAP foods and liver cancer, with mediation proportions calculated accordingly. MR analyses revealed that higher consumption of cheese (OR = 0.548, 95% CI = 0.404-0.743), fresh fruit (OR = 0.375, 95% CI = 0.194-0.727), cereal (OR = 0.575, 95% CI = 0.386-0.857), and dried fruit (OR = 0.539, 95% CI = 0.340-0.853) was significantly associated with a reduced risk of liver cancer. Protein-level analyses identified four trogocytosis- and efferocytosis-related proteins, TGFB3, EPOR, ELANE, and C3, that may mediate these dietary effects on liver cancer susceptibility. Mediation MR indicated that cheese intake influenced liver cancer risk indirectly by modulating TGFB3, EPOR, ELANE, and C3 expression, accounting for 8.8%, 25%, 1.8%, and 12.7% of the total effect, respectively. Sensitivity analyses for heterogeneity and pleiotropy supported the robustness of these findings. This study uncovers a potential molecular mechanism by which FODMAP-related dietary patterns may modulate liver cancer risk through the TGFB3/EPOR/ELANE/C3 signaling axis. These results provide genetic evidence and mechanistic insights supporting the role of FODMAP-oriented dietary strategies in liver cancer prevention, offering a theoretical basis for future public health interventions.