Work

Site-specific N-glycosylation of alpha-2-macroglobulin reflects the progression of Schistosoma japonicum-induced liver fibrosis

Year: 2026

Type: article

Abstract: 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 Schistosoma japonicum-induced liver fibrosis (SjLF), aiming to identify site-specific glycosylation markers for fibrosis monitoring. A longitudinal rabbit model of Schistosoma japonicum 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. 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. This study provides insights into dynamic remodeling of host protein N-glycosylation during Schistosoma japonicum –induced liver fibrosis and highlights its critical role in schistosome–host interactions. Schistosomiasis, a tropical parasitic disease, causes liver fibrosis when worms infect the liver and deposit eggs, triggering chronic inflammation and scar tissue buildup. Scientists knew that the parasites use protective sugar molecules on their surface to evade immunity—but how host sugar modification, known as glycosylation, changes during infection remained unclear. We analyzed blood samples from schistosome-infected rabbits and found stage-specific glycosylation changes on immune-related proteins. Notably, a protein called A2M showed dramatic changes to the sugars across its surface; one change strongly correlated with fibrosis severity and accurately distinguished patients with schistosomiasis-related liver fibrosis. These findings reveal that infection reprograms host protein glycosylation—not merely triggering inflammation, but reshaping a glycan-mediated host–parasite interface—enabling non-invasive, blood-based monitoring of this neglected tropical disease. Zhao et al. profile serum glycosylation across a longitudinal rabbit model of Schistosoma japonicum infection and liver fibrosis, additionally validating candidate biomarkers in clinical serum. They show that site-specific N-glycosylation on alpha-2-macroglobulin, especially at N1424, tracks fibrosis stage and serves as a promising blood biomarker panel.

Source: Communications Medicine

DOI: 10.1038/s43856-026-01826-w