Enzymatic Site-Selective Deglycosylation Enhances PPM1A Agonistic Activity of Dammarane Saponins for the Treatment of Hepatic Fibrosis.

Carbohydrate moieties profoundly influence target binding, drug-like properties, and mechanism of action, but achieving site-selective editing within complex oligosaccharide chains remains a challenge for conventional chemical methods. We herein report an enzymatic deglycosylation platform that enables precise, site-selective removal of sugar units from branched carbohydrate chains of dammarane-type saponins, the first reported PPM1A phosphatase agonists. SAR analysis confirms the distal xylose removal drastically improves PPM1A agonistic potency versus the parent saponins. Cellular and in vivo assays prove the optimized derivative represses PPM1A-governed TGF-β1/Smad3 and NF-κB p65 phosphorylation. In diverse hepatic fibrosis models, it alleviates fibrotic progression dose-dependently, matching the efficacy of the clinical drug resmetirom at equivalent doses and administration regimens. In conclusion, our findings establish a versatile toolbox for precise modifications of complex carbohydrate moieties under mild conditions and delineate the critical role of specific glycosyl groups in modulating PPM1A activity as a therapeutic strategy for hepatic fibrosis.