Novel genetic insights into causal effects of depression on non-alcoholic fatty liver diseases partially mediated by gut microbiota.

Depression and non-alcoholic fatty liver disease (NAFLD) are increasingly recognized as interconnected disorders, yet the causal mechanisms linking them remain unclear. Using univariable and multivariable Mendelian randomization (MR), we demonstrated that depression causally increased the risk of NAFLD (P = 8.473 × 10-8, OR = 1.944, 95% CI: 1.524 to 2.479), independent of major metabolic confounders. Mediation analysis further identified the gut microbial genus Phascolarctobacterium as a partial mediator of this effect (P = 0.0328, β = 0.145, 95% CI: 0.0119 to 0.278), with a mediated proportion of 21.818%. By integrating genetic mapping, transcriptomic profiling, and machine learning, we identified MICAL2 as a central hub gene linking depression-associated genetic variation to NAFLD. Furthermore, single-cell analysis revealed MICAL2-associated gene signatures are linked to macrophage dysfunction in NAFLD. Besides, molecular docking and dynamics simulations suggested that sanguinarine might target MICAL2 with stable binding affinity, highlighting a potential therapeutic avenue. Finally, experimental validation confirmed MICAL2 overexpression in liver tissues of NAFLD mouse models. Together, our findings support a mechanistic framework in which depression promotes NAFLD through a microbiota-mediated pathway converging on MICAL2 and macrophage dysfunction. These findings might have implications for risk stratification and early intervention of depression-induced NAFLD patients and offer novel insights into the brain-gut-liver interactions.