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

ABSTRACT

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.