Regulation of lipoprotein processing by GPNMB in foamy macrophages: potential therapeutic targets for atherosclerosis

Junqi Wang, Liming Peng, Huan Wang, Di Liu, Wenting Yang, Fang Yan, Dianyuan Zhao, Chunhua Zhang, Ziliang He, Xiao-Ping Chen () and Li Tang ()
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Junqi Wang: Beijing Institute of Lifeomics
Liming Peng: Central South University
Huan Wang: Beijing Institute of Lifeomics
Di Liu: Beijing Institute of Lifeomics
Wenting Yang: Beijing Institute of Lifeomics
Fang Yan: Beijing Institute of Lifeomics
Dianyuan Zhao: Beijing Institute of Lifeomics
Chunhua Zhang: Beijing Institute of Lifeomics
Ziliang He: Guangzhou
Xiao-Ping Chen: Central South University
Li Tang: Beijing Institute of Lifeomics

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: Abstract The formation of foamy macrophages is often considered a pathological hallmark of atherosclerosis, but the underlying mechanisms remain elusive. Herein, we demonstrated that the transcription factor TFEC could upregulate the expression of Glycoprotein non-metastatic melanoma protein B (GPNMB) in atherosclerotic plaque foamy macrophages. Circulating levels of soluble GPNMB correlated positively with atherosclerotic severity. Moreover, mice with systemic Gpnmb-mutation or myeloid-specific Gpnmb knockout exhibited a reduced atherosclerotic burden. Live-cell imaging revealed that GPNMB-positive vesicles were involved in lipoprotein internalization and transport within macrophages and facilitated lipid droplet formation. In Gpnmb-mutant macrophages, impaired lipid droplet formation from internalized lipoproteins, combined with enhanced lipid β-oxidation and lysosomal lipolysis, led to reduced macrophage foaming. Notably, mice treated with siRNA-loaded lipid nanoparticles targeting Gpnmb in lesional foamy macrophages showed alleviation of atherosclerotic burden. Overall, our findings elucidate the intracellular lipoprotein processing in macrophages and suggest GPNMB as a potential therapeutic target for atherosclerosis.

Date: 2025
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DOI: 10.1038/s41467-025-65224-x

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