Background <p>Schistosomiasis-induced liver fibrosis arises from egg-driven granulomatous inflammation. While parasite glycosylation facilitates immune evasion and disease progression, host protein glycosylation remodeling during hepatic fibrogenesis remains elusive. Here, temporal serum glycosylation profiles were characterized across infection stages in a rabbit model of <i>Schistosoma japonicum</i>-induced liver fibrosis (SjLF), aiming to identify site-specific glycosylation markers for fibrosis monitoring.</p> Methods <p>A longitudinal rabbit model of <i>Schistosoma japonicum</i> infection and liver fibrosis was established, and serum glycosylation patterns were profiled using lectin microarrays, followed by site-specific glycoproteome characterization via high-resolution mass spectrometry (MS). Candidate markers were subsequently evaluated in a clinical serum cohort through targeted parallel reaction monitoring–mass spectrometry (PRM-MS) with predefined glycopeptide signals.</p> Results <p>Temporal serum glycosylation profiling reveals dynamic increases in sialylation and fucosylation during SjLF progression to late fibrosis. Intact glycopeptide analysis further reveals stage-dependent alterations in N-glycosylation of humoral immune response proteins, most notably involving site-specific glycosylation of alpha-2-macroglobulin (A2M). Ten A2M glycosylation sites show significant inter-stage variation, supporting their biomarker potential. Subsequent validation in clinical serum samples confirms A2M-N₁₄₂₄QT glycopeptide as a robust diagnostic indicator for SjLF, demonstrating targeted glycoproteomics as a precision monitoring strategy.</p> Conclusion <p>This study provides insights into dynamic remodeling of host protein N-glycosylation during <i>Schistosoma japonicum</i> –induced liver fibrosis and highlights its critical role in schistosome–host interactions.</p>