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

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.