Structural characterization and anti-lung cancer activity of fucoidans derived from Saccharina japonica

Fucoidans from Saccharina japonica are structurally diverse polysaccharides whose biological activities are strongly influenced by molecular size, branching, and sulfation patterns. In this study, 18 fractions were isolated from kelp collected across different seasons using hot-water and acid extraction, with yields of 0.6%-1.7%. The water-extracted fractions (SJ-W) contained higher total sugar and uronic acid levels, whereas the acid-extracted fractions (SJ-S) were enriched in fucose and axial C4 sulfation. A sulfated galactofucan fraction, SJ-W-3, was subjected to autohydrolysis, yielding a low-molecular-weight sulfated fraction, SF (6.1 kDa; 26.8% yield), and a high-molecular-weight counterpart, SJ-W-3-H (201.1 kDa; 53.6% yield). SF was over-sulfated to produce the derivative SF-PS (6.7 kDa). In A549 xenograft nude mice, SJ-W-3 and SJ-W-3-H exhibited strong anti-tumor activity, reducing tumor weight from 0.75 g to 0.36 g. By contrast, SF and SF-PS showed weaker effects, with tumor weights of 0.49 and 0.53 g, corresponding to inhibition rates of 34.4% and 28.9%, respectively. These findings indicate that additional C2 sulfation did not further enhance anti-tumor activity. Quantitative proteomic profiling identified 141 upregulated and 135 downregulated proteins, suggesting suppression of tumor-promoting proteins, including LCN2, CD36, CSF1R, and MMP9, and increased expression of tumor-suppressive proteins, including BAD, HPGD, and HTATIP2. Molecular docking further suggested that C4-linked sulfation supported more stable interactions with selected protein pockets. Overall, high-molecular-weight, branched fucoidans enriched in C4 sulfation appear to be the structural features most closely associated with the anti-tumor potential of S. japonica, whereas additional C2 sulfation in the low-molecular-weight SF fraction did not improve anti-tumor efficacy.