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<p>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 <i>Gpnmb-</i>mutation or myeloid-specific <i>Gpnmb</i> 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 <i>Gpnmb</i>-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 <i>Gpnmb</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月14日

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  • Junqi Wang,
  • Liming Peng,
  • Huan Wang,
  • Di Liu,
  • Wenting Yang,
  • Fang Yan,
  • Dianyuan Zhao,
  • Chunhua Zhang,
  • Ziliang He,
  • Xiao-Ping Chen,
  • Li Tang

摘要

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.