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Targeting cytokine-like protein FAM3D alleviates atherosclerosis

Shirong Zhu1, Minzhe Zhu1, Fangfang Fan2

  • 1Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China.

Cell Reports. Medicine
|July 1, 2026
PubMed

Insights

Elevated FAM3D protein levels worsen atherosclerosis by promoting cholesterol absorption and vascular cell changes. Targeting FAM3D with antibodies offers a new approach to reduce cardiovascular risk beyond statins.

Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Atherosclerosis Research

Background:

  • Residual cardiovascular risk persists despite effective cholesterol-lowering drugs.
  • Atherosclerosis remains a major cause of cardiovascular disease.
  • The role of cytokine-like protein FAM3D in atherosclerosis is unexplored.

Purpose of the Study:

  • To investigate the contribution of FAM3D to the development of atherosclerosis.
  • To elucidate the mechanisms by which FAM3D influences atherosclerosis.
  • To evaluate FAM3D as a potential therapeutic target.

Main Methods:

  • Analysis of clinical cohort data for FAM3D levels and atherosclerosis association.
  • Utilizing global and intestinal epithelial cell-specific Fam3d-deficient mouse models.
  • Investigating FAM3D's effects on intestinal lipid absorption and chylomicron assembly.
  • Examining FAM3D-induced vascular smooth muscle cell (VSMC) dedifferentiation.
  • Assessing the role of the formyl peptide receptor 1 (FPR1) signaling pathway.
  • Testing the efficacy of anti-FAM3D monoclonal antibodies in mouse models.

Main Results:

  • Elevated circulating FAM3D levels correlate strongly with human atherosclerosis.
  • Fam3d deficiency in mice significantly reduces atherosclerosis and intestinal lipid absorption.
  • FAM3D upregulates microsomal triglyceride transfer protein (MTTP) and promotes chylomicron assembly.
  • Endothelial FAM3D induces VSMC dedifferentiation via a lipid-independent pathway.
  • FPR1-Gαi/Gαq signaling mediates FAM3D's effects.
  • Anti-FAM3D antibodies mitigate atherosclerosis in mice.

Conclusions:

  • FAM3D exacerbates atherosclerosis through both lipid-dependent and lipid-independent mechanisms.
  • FAM3D represents a promising therapeutic target for residual cardiovascular risk.
  • Targeting FAM3D may offer a novel strategy beyond current lipid-lowering therapies.

Keywords:
FAM3Datherosclerotic cardiovascular disease residual riskformyl peptide receptor 1intestinal lipid absorptionmonoclonal antibodiesvascular smooth muscle cell dedifferentiation

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