B4galnt3, which expresses the enzyme beta-1,4-N-acetylgalactosaminyltransferase 3, is crucial for transferring N-acetylgalactosamine onto N-acetylglucosamineβ-benzyl on protein epitopes (LDN-glycosylation). This process is involved in multiple biological pathways, such as those related to glycoprotein functions, bone physiology, and cell-cell interactions. Genetic models, like knockout mice, have been valuable for studying its functions [1,2].

In B4galnt3-/-mice, higher circulating sclerostin levels were observed, yet serum levels of LDN-glycosylated sclerostin were lower, leading to lower bone mass. This established B4galnt3 as a causal gene for circulating sclerostin levels and demonstrated its key role in bone physiology via sclerostin glycosylation [1]. In neuroblastoma cells, re-expression of B4galnt3 suppressed cell proliferation, colony formation, migration, and invasion, indicating its role in suppressing the malignant phenotype [3]. In colon cancer cells, knockdown of B4galnt3 decreased sphere formation and the expression of stem cell markers, suggesting its involvement in regulating cancer stemness [4].

In conclusion, B4galnt3 is essential for LDN-glycosylation, which impacts diverse biological processes. Studies using B4galnt3 knockout mouse models have revealed its significance in bone-related diseases, as well as in cancer, including neuroblastoma and colon cancer, by influencing cell behavior and protein glycosylation. These findings contribute to understanding disease mechanisms and potentially developing targeted therapies.