Targeting cytokine-like protein FAM3D alleviates atherosclerosis.

Despite effective cholesterol-lowering medications, significant residual cardiovascular risk related to atherosclerosis remains. Here, we explore whether the cytokine-like protein FAM3D contributes to atherosclerosis. Clinical cohort data reveal that elevated circulating FAM3D levels are strongly associated with human atherosclerosis. Both global and intestinal epithelial cell-specific Fam3d deficiencies significantly inhibit intestinal cholesterol and triglyceride absorption and mitigate atherosclerosis in mice. Mechanistically, FAM3D upregulates microsomal triglyceride transfer protein (MTTP) expression and activity, promoting chylomicron assembly in intestinal epithelial cells. Meanwhile, endothelial FAM3D induces vascular smooth muscle cell (VSMC) dedifferentiation via a lipid-independent mechanism. Both effects are mediated by the formyl peptide receptor 1 (FPR1)-Gαi/Gαq signaling cascade. Importantly, two monoclonal antibodies targeting FAM3D effectively suppress intestinal MTTP-mediated chylomicron assembly and VSMC dedifferentiation, thereby mitigating atherosclerosis in mice. In conclusion, FAM3D exacerbates atherosclerosis through both lipid-dependent and lipid-independent mechanisms, representing a promising therapeutic target for combating residual cardiovascular risk unresolved by current cholesterol-lowering therapies.