TMAO has been suggested to not only regulate cholesterol balance and bile acid levels but is also associated with early atherosclerosis and high long-term mortality risk of CVDs.131 Mechanistically, TMAO can activate the mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways in endothelial cells and smooth muscle cells.132 The MAPK signaling pathway can be stimulated by growth factors, pathogen-associated molecules, and inflammatory cytokines, which follows by a MAPKKK-MAPKK-MAPK-TFs signaling cascade and results in the expression of inflammatory cytokines IL-6, IL-8, and TNF-α. The gene discussed is NFKB1; the disease is atherosclerosis.