Structural characterization and protective effects of an <em>Apostichopus japonicus</em> -derived fucoidan against lipopolysaccharide-induced acute lung inflammation

Acute lung inflammation (ALI) poses a significant global health challenge. Conventional synthetic anti-inflammatory drugs often show limited efficacy against ALI and may cause side effects. Natural fucoidans exhibit promising anti-inflammatory properties, but their specific effects and mechanisms in ALI remain unclear. In this study, we characterized the structural features of&nbsp;<em>Apostichopus japonicus</em>-derived fucoidan&nbsp;<strong>AJ2-I</strong>&nbsp;using methylation analysis, 1D/2D nuclear magnetic resonance, and chemical assays. We then evaluated its anti-ALI effects in lipopolysaccharide-challenged C57BL/6J mice and human A549 cells. Structural analysis revealed that&nbsp;<strong>AJ2-I</strong>&nbsp;primarily consists of [→3)-Fucp-(1→] residues with C4 branching, while sulfate groups were predominantly substituted at C2 and C4 positions. Notably, this fucoidan contains unique glycosyls—→4)-β-D-GalpA-6-O-Et-(1→ and →4)-β-D-GalpA-6-OMe-(1→—distinguishing it from previously reported&nbsp;<em>A. japonicus</em>&nbsp;polysaccharides. Functionally,&nbsp;<strong>AJ2-I</strong><strong>&nbsp;</strong>significantly suppressed pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) in both&nbsp;<em>in vivo</em>&nbsp;and&nbsp;<em>in vitro</em>&nbsp;models. Mechanistically, it inhibited <strong>Toll-like receptor 2/4</strong> to suppress<strong>&nbsp;mitogen-activated protein kinase</strong> and<strong>&nbsp;phosphoinositide-3 kinase/protein kinase B&nbsp;</strong>signaling pathways, thereby blocking the activation of key transcription factors, including&nbsp;<strong>nuclear factor kappa-B</strong><strong>&nbsp;</strong>and<strong>&nbsp;c-Jun/activator protein-1</strong>. These findings elucidate the protective role of&nbsp;<em>A. japonicus</em>-derived fucoidan <strong>AJ2-I</strong> in ALI and uncover its underlying molecular mechanisms, supporting the potential use of fucoidans in treating lung inflammation.