Gpnmb, also known as glycoprotein nonmetastatic melanoma protein B, is an endogenous glycoprotein. It is highly expressed in macrophages and microglia, participating in innate immune responses. Its functions seem to be related to inflammation, metabolism, and cancer progression, with potential implications in neurodegenerative diseases [1,3,4].

In Parkinson's disease, colocalization and allele-specific expression studies linked the GWAS-derived chromosome 7 locus to Gpnmb. In induced pluripotent stem cell-derived neurons, loss of Gpnmb led to loss of ability to internalize α-synuclein fibrils and develop α-synuclein pathology, and Gpnmb was elevated in PD plasma, associating with disease severity [2].

In the context of obesity, inhibition of the hepatic sterol regulatory element-binding protein pathway increased Gpnmb transcription, and Gpnmb promoted lipogenesis in white adipose tissue, exacerbating diet-induced obesity and insulin resistance. Inhibition of Gpnmb improved metabolic parameters, likely by promoting the beiging of white adipose tissue [3].

In cancer, macrophage-derived soluble Gpnmb increased tumor growth and metastasis in Gpnmb-mutant mice, triggered the formation of self-renewing spheroids in cancer cells, and activated a paracrine axis with IL-33 to promote cancer cell survival and metastasis [5].

In conclusion, Gpnmb plays diverse roles in biological processes such as inflammation, neurodegenerative diseases, metabolism, and cancer. Studies using gene-knockout models in mice have been crucial in revealing these functions, especially in Parkinson's disease, obesity, and cancer, providing insights into potential therapeutic targets for these diseases.