Molecular Perspective of GPNMB in the Progression of End-Stage Liver Disease

Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) is an emerging transmembrane glycoprotein involved in inflammation, immune modulation, and tumor progression in liver cancer. The liver is one of the most vital organs, where various metabolic pathways occur in the synthesis of macromolecules and micro molecules, and is involved in different nuclear metabolic changes. Unhealthy diets, obesity and inadequate exercise are global concerns that lead to cardiometabolic, diabetes and end-stage liver disease. Thus, to elucidate the structural aberrations of GPNMB via various routes, such as a wide array of proteogenic domains, RGD (Arg-Gly-Asp), PKD (Polycystic Kidney Domain), and hemITAM (Half immunoreceptor tyrosine-based activation) domains. They are closely associated with inflammation, immune modulation, and the sculpting of the liver microenvironment, which leads to the progression of steatohepatitis to HCC. Approximately 70–80% of HCC accounts for all chronic liver disease through the alteration of GPNMB activity with the mTOR, NF-κB, PI3K/AKT, and JAK/STAT pathways in the progression of cancer. This review provides comprehensive insights into GPNMB, a transmembrane protein actively involved in epigenetic regulation during disease progression from steatohepatitis to cirrhosis and ultimately to end-stage liver disease. The graphical Abstract is shown below: GPNMB promotes HCC by regulating inflammation, immunological responses, and tumor growth through critical pathways via mTOR, PI3K/Akt, JAK/STAT, and TGF-β.