Vascular-specific FAM43B inhibits the Wnt pathway by regulating β-catenin ubiquitination and alleviates the progression of atherosclerosis.

Authors

Yunkai Wang, Xiaoyang Li, Yeshun Wu, Hanzhong Zhang, Wenbing Jiang, Jingyong Huang

Published in

Life sciences. Pages 124721. Oct 05, 2026. Epub Oct 05, 2026.

Abstract

Current therapies cannot completely halt atherosclerotic plaque progression and plaque destabilization, making it critical to discover core genes maintaining vascular homeostasis. Preliminary transcriptomic data revealed that FAM43B is enriched in vascular endothelial and smooth muscle cells, yet its cardiovascular roles remain unknown. This study elucidates how FAM43B controls endothelial homeostasis and drives atherosclerosis progression.
We used human vascular single-cell transcriptomics and X-Gal staining to characterize FAM43B expression and its inhibitory pathological triggers. Three bidirectional mouse models (global knockout, vascular conditional knockout, AAV-mediated local overexpression) were established to assess atherosclerotic phenotypes. HUVEC transcriptome sequencing and cellular molecular assays further explored FAM43B-β-catenin interaction and the ubiquitination mechanism governing canonical Wnt/β-catenin signaling.
FAM43B selectively expressed in endothelial and smooth muscle cells, and is suppressed by disturbed flow, vascular aging, IL-1β and TNF-α. FAM43B deletion worsens aortic lipid deposition, intimal hyperplasia and plaque vulnerability in mice, while vascular FAM43B overexpression restrains aberrant Wnt signaling, reduces inflammation and lipid buildup, and stabilizes plaques. Mechanistically, FAM43B directly binds β-catenin, facilitates protective K63 ubiquitination to suppress Wnt activity. Smooth muscle FAM43B loss also hyperactivates Wnt signaling, triggering cell dedifferentiation, pro-inflammatory cytokine and matrix protease release to destabilize plaques. Low FAM43B expression inhibits Wnt pathway suppression, leading to vascular injury, inflammation and higher plaque rupture risk.
This work identifies FAM43B as a central protective gene against atherosclerosis in vascular wall cells. Upregulating FAM43B suppresses pathological Wnt/β-catenin activation, mitigates vascular inflammation and lipid deposition, and improves plaque stability, offering a promising new therapeutic target for atherosclerosis prevention and treatment.

PMID:
42833574
Bibliographic data and abstract were imported from PubMed on 06 Oct 2026.

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