• CD98hc is identified as a novel binding partner for galectin-8 (Gal-8), expanding the known repertoire of Gal-8 receptors.
• The interaction between CD98hc and Gal-8 is N-glycosylation-dependent, as demonstrated by inhibition with tunicamycin and pull-down assays.
• Both N- and C-terminal carbohydrate recognition domains (CRDs) of Gal-8 bind to CD98hc, with distinct affinities (Gal-8N: 0.22 μM; Gal-8C: 10.68 μM).
• The binding is specifically inhibited by lactose, indicating β-galactoside specificity, and may have implications for Gal-8-mediated cellular functions.