Integrated Glycoproteomics Identifies Dynamic IgA1 N‐Glycosylation and FUT8 as a Functional Mediator in Multiple Myeloma

Aberrant protein glycosylation is pivotal in cancer progression. However, the IgA glycosylation landscape in multiple myeloma (MM) and its regulatory mechanisms remain uncharacterized. We conducted a comprehensive glycoproteomic analysis of site-specific N-glycosylation at IgA1-Asn144 across a large cohort, including newly diagnosed MM patients (n = 50), healthy controls (n = 38), and longitudinal samples from various remission stages. Analysis was performed using Zeno trap-equipped time-of-flight mass spectrometry. We identified a significant upregulation of fucosylated N-glycopeptides in MM. A diagnostic model based on two fucosylated glycopeptides showed potential diagnostic utility (AUC = 0.808). Attaining deep therapeutic remission was associated with a marked loss of fucosylation and downregulation of hypersialylated glycans. Bioinformatics analysis pinpointed the fucosyltransferase FUT8 as a key differentially expressed regulator, which was subsequently validated to be elevated in MM at both RNA and protein levels. FUT8 promotes tumor progression by activating Wnt/β-catenin signaling and EMT-associated pathways, thereby enhancing MM cell proliferation, migration, and invasiveness. These findings identify FUT8 as a potential prognostic biomarker and a therapeutic target in MM.