Targeting cytokine-like protein FAM3D alleviates atherosclerosis PMID: 42385709

GLP-1 and Obesity Research

2026-08-18

Targeting cytokine-like protein FAM3D alleviates atherosclerosis

Cell Rep Med. 2026 Jul 21;7(7):102908. doi: 10.1016/j.xcrm.2026.102908.

Shirong Zhu ¹ , Minzhe Zhu ¹ , Fangfang Fan ² , Zeyu Cai ¹ , Yicong Shen ³ , Zhuofan Li ¹ , Qianhui Ding ¹ , Xi Wang ¹ , Zhao Dong ¹ , Zhenkun Huang ¹ , Sen Lin ¹ , Siting Zhang ¹ , Fang Yu ¹ , Jia Jia ² , Jiaai Tan ¹ , Jianzhong Xi ⁴ , Wei Kong ⁵ , Yan Zhang ⁶ , Yi Fu ⁷

Affiliations

1. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China.
2. Department of Cardiology, Institute of Cardiovascular Disease, Peking University First Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100034, China.
3. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China; Department of Pathophysiology, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China.
4. Department of Biomedicine, College of Engineering, Peking University, Beijing 100871, China.
5. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China. Electronic address: [email protected].
6. Department of Cardiology, Institute of Cardiovascular Disease, Peking University First Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100034, China. Electronic address: [email protected].
7. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China; Medical Innovation Center (Taizhou) of Peking University, Taizhou, Jiangsu 225316, China. Electronic address: [email protected].

Abstract

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)-G_αi/G_αq 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.

Keywords

FAM3D; atherosclerotic cardiovascular disease residual risk; formyl peptide receptor 1; intestinal lipid absorption; monoclonal antibodies; vascular smooth muscle cell dedifferentiation.