UDP-Gal-β-1,4 galactosyltransferase-V (GalT-V) is a member of a large family of galactosyltransferases whose function is to transfer galactose from the nucleotide sugar UDP-galactose to a glycosphingolipid glucosylceramide, to generate lactosylceramide (LacCer). It also causes the N and O glycosylation of proteins in the Trans Golgi area. LacCer is a bioactive lipid second messenger that activates an “oxidative stress pathway”, leading to critical phenotypes, e.g., cell proliferation, migration angiogenesis, autophagy, and apoptosis. It also activates an “inflammatory pathway” that contributes to the progression of disease pathology. β-1,4-GalT-V gene expression is regulated by the binding of the transcription factor Sp-1, one of the most O-GlcNAcylated nuclear factors. This review elaborates the role of the Sp-1/GalT-V axis in disease phenotypes and therapeutic approaches targeting not only Sp-1 but also Notch-1, Wnt-1 frizzled, hedgehog, and β-catenin. Recent evidence suggests that β-1,4GalT-V may glycosylate Notch-1 and, thus, regulate a VEGF-independent angiogenic pathway, promoting glioma-like stem cell differentiation into endothelial cells, thus contributing to angiogenesis. These findings have significant implications for cancer and cardiovascular disease, as tumor vascularization often resumes aggressively following anti-VEGF therapy. Moreover, LacCer can induce angiogenesis independent of VEGF and its level are reported to be high in tumor tissues. Thus, targeting both VEGF-dependent and VEGF-independent pathways may offer novel therapeutic strategies. This review also presents an up-to-date therapeutic approach targeting the β-1,4-GalT-V interactome. In summary, the β-1,4-GalT-V interactome orchestrates a broad network of signaling pathways essential for maintaining cellular homeostasis. Conversely, its dysregulation can promote unchecked proliferation, angiogenesis, and inflammation, contributing to the initiation and progression of multiple diseases. Environmental factors and smoking can influence β-1,4-GalT-V expression and its interactome, whereas elevated β-1,4-GalT-V expression may serve as a diagnostic biomarker of colorectal cancer, inflammation—exacerbated by factors that may worsen pre-existing cancer malignancies, such as smoking and a Western diet—and atherosclerosis, amplifying disease progression. Increased β-1,4-GalT-V expression is frequently associated with tumor aggressiveness and chronic inflammation, underscoring its potential as both a biomarker and therapeutic target in colorectal and other β-1,4-GalT-V-driven cancers, as well as in cardiovascular and inflammatory diseases.

Cardiovascular disease (CVD) is the leading cause of death worldwide, yet roughly 70% of major adverse cardiovascular events occur in statin-treated patients with optimized Low-density lipoprotein cholesterol (LDL-C), a gap that cholesterol-based risk panels do not close. Ceramides are bioactive sphingolipids whose plasma species and ratios carry risk information absent from standard lipid panels, and ceramide-based scores (CERT and CERT2) are already in clinical use. Whether this value extends beyond CVD is unclear. We reviewed ceramide species and ratios as biomarkers for disease prediction, prognosis, and disease activity across cardiovascular, metabolic, autoimmune rheumatic, inflammatory bowel, pulmonary, kidney, and oncologic contexts, searching PubMed and Scopus from January 1990 to June 2026 and extending the search for the historical literature. In CVD, CERT and CERT2 predicted cardiovascular events and mortality independently of LDL cholesterol, including in statin-treated and kidney disease populations. In metabolic and autoimmune rheumatic disease, ceramide profiles tracked cardiovascular risk and disease activity. In inflammatory bowel disease, chronic obstructive pulmonary disease, and most cancers, the evidence is mechanistically strong but limited to single-cohort or observational studies. Ceramides are emerging biomarkers that complement, not replace, established risk tools. Broader clinical use requires prospective validation, diverse cohorts, standardized assays, and demonstrated cost-effectiveness.