QCAR Model-Guided Optimization of a Hepatoprotective Ganoderma lucidum Polysaccharide: Targeted Preparation, Structural Characterization, and Gut-Liver Axis Regulation
Description
Natural polysaccharides are promising candidates for the management of alcohol liver disease (ALD), yet their structural complexity hinder structure-activity relationship analysis. Here, a QCAR model was established based on monosaccharide composition and literature-reported hepatoprotective efficacy data, with MATLAB-based regression analyses and leave-one-out cross-validation identifying Glc as a robust positive compositional predictor. Subsequently, the QCAR model guided carbon-source optimization and chromatographic purification to obtain the Glc-enriched polysaccharide GLP-1A from Ganoderma lucidum. Preliminary analysis indicated that GLP-1A had a molecular weight of 10.38 MDa and contained 95.05 mol% Glc, with minor Man, Gal, and Fuc. Importantly, the model predicted a 47.86% reduction in the ALT/AST-based efficacy score, closely matching the experimentally observed 49.82% reduction (relative deviation, 4.09%). Comprehensive structural characterization by monosaccharide composition analysis, methylation analysis and NMR spectroscopy revealed GLP-1A was a branched heteropolysaccharide dominated by a →4)-α-D-Glcp-(1→ backbone, with →3,4)- and →4,6)-linked Glcp branch points and terminal α-D-Galp, α-D-Manp, and α-L-Fucp residues. Finally, GLP-1A alleviated chronic alcohol-induced hepatic injury and inflammation, accompanied by a reduction in LPS-carrying fecal extracellular vesicles (fEVs) which led to attenuation of the Caspase-11/GSDMD pathway. These findings validate QCAR-guided polysaccharide optimization and support a potential role of fEV-carried LPS in gut-liver inflammatory signaling.
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Institutions
- Shandong University of Traditional Chinese MedicineShandong, Jinan