Work

SLC35A3 Remodels Site-Specific N-Glycosylation and Defines a Druggable Glycosylation Target in Hepatocellular Carcinoma

Year: 2026

Type: article

Abstract: Aberrant N-glycosylation contributes to hepatocellular carcinoma (HCC) progression, yet the upstream regulators that coordinate nucleotide-sugar transport and site-specific N-glycosylation remain poorly characterized. Here, we identified SLC35A3, a Golgi-resident UDP-GlcNAc transporter, as a glycosylation-related tumor suppressor in HCC. SLC35A3 was downregulated in HCC tissues, and its restoration suppressed cell proliferation and tumorigenicity. Mechanistically, SLC35A3 overexpression increased Golgi-resident UDP-GlcNAc levels, indicating enhanced substrate availability for glycosyltransferases. Intact N-glycopeptide profiling demonstrated that SLC35A3 overexpression reprogrammed site-specific N-glycan processing, characterized by a predominant reduction in high-mannose (HM) glycoforms and selective remodeling of fucosylated-sialylated (FS) glycoforms. Molecular docking identified poliumoside as a putative SLC35A3 binder with anti-tumor effect in HCC models. Together, our findings establish SLC35A3 as a critical node in Golgi-dependent N-glycan remodeling and highlight its potential as a target for pharmacological activation.

Source: Molecular & Cellular Proteomics

DOI: 10.1016/j.mcpro.2026.101672