St3gal6, also known as ST3 β -galactoside α2,3 -sialyltransferase 6, is a significant glycosyltransferase responsible for adding α2,3 -linked sialic acid to substrates and generating glycan structures. Sialylation, the process it is involved in, is an essential form of glycosylation, and in the nervous system, abnormal sialylation can impact various physiological processes [3]. The St3gal6 -related pathways have been associated with PI3K/Akt, autophagy, and EGFR signaling, among others, and play important roles in cancer progression, autophagy regulation in hepatic encephalopathy, and cell biological function regulation [1,3,4]. Genetic models are valuable for studying its functions.

In multiple myeloma, knockdown of St3gal6 led to a significant reduction in levels of α-2,3 -linked sialic acid on the cell surface, along with reduced adhesion to bone marrow stromal cells and fibronectin, and decreased transendothelial migration in vitro. In vivo, this also resulted in reduced homing and engraftment of cells to the bone marrow niche, decreased tumor burden, and prolonged survival, highlighting its importance in cell adhesion and migration [7].

In hepatocellular carcinoma, the upregulation of St3gal6 was correlated with cell proliferation, migration, and invasion ability, and miR-26a negatively regulated St3gal6, suppressing these cell behaviors through the Akt/mTOR pathway [5].

In colorectal cancer, St3gal6 levels were lower in tumor tissues, and the lncRNA St3gal6-AS1 recruited histone methyltransferase to the promoter region of St3gal6, inducing its transcription, and the St3gal6-AS1/St3gal6 axis mediated α-2,3 sialylation and inhibited PI3K/Akt signaling [1].

In gastric cancer, circSt3gal6 was significantly downregulated and overexpression of it inhibited the malignant behaviors of GC cells by inducing apoptosis and autophagy [2].

In lung adenocarcinoma, the downregulation of St3gal6 promoted cell invasiveness with activated EGFR/MAPK signaling [6].

In hepatic encephalopathy, silencing St3gal6 and blocking or degrading α2,3 -sialylated glycans inhibited autophagy, and St3gal6 regulated autophagy through the HSPB8-BAG3 complex [3].

In cell lines, knockout of St3gal6 decreased cell proliferation and colony formation, suppressed the phosphorylation level of ERK, enhanced cell aggregations and the expression levels of E-cadherin and claudin-1, and decreased the α2,3 -sialylation levels of EGFR [4].

In conclusion, St3gal6 plays crucial roles in multiple biological processes, especially in various cancer-related phenotypes such as cell proliferation, metastasis, and apoptosis, as well as autophagy regulation in hepatic encephalopathy. Studies using gene knockout or knockdown models in multiple myeloma, hepatocellular carcinoma, colorectal cancer, gastric cancer, lung adenocarcinoma, and in cell lines have significantly contributed to revealing these functions, providing insights into potential therapeutic targets for related diseases.