Molecular weight-dependent hepatoprotection of American ginseng polysaccharides

Liver injury represents a major global health burden, often initiated by oxidative stress, which subsequently triggers inflammatory cascades and apoptotic cell death. Polysaccharides from American ginseng (Panax quinquefolius L.) (AGPs) have demonstrated immunomodulatory and antioxidant properties. However, the hepatoprotective mechanisms of purified AGP fractions remain inadequately understood.

Two polysaccharide fractions, AGP₁ (>100 kDa) and AGP₂ (<10 kDa), were extracted, purified, and characterized. Neither fraction induced histopathological abnormalities in the major organs of healthy mice after daily intragastric administration at 200 mg kg^-1 for 14 consecutive days. Their hepatoprotective efficacy was compared in a CCl₄-induced acute liver injury mouse model. Both fractions dose-dependently reversed these alterations, with AGP₂ consistently outperforming AGP₁ at equivalent doses. Compared with the model group, high-dose AGP₂ (200 mg kg^-1) reduced serum aspartate aminotransferase and malondialdehyde by 36% and 45%, respectively, increased hepatic superoxide dismutase activity 1.3-fold (to 585.4 ± 45.2 U mg^-1 protein), and lowered serum TNF-α and IL-6 by 39% and 38%, respectively (to 578.6 ± 22.8 and 112.5 ± 7.2 pg mL^-1). These effects not only surpassed those of both low- and high-dose AGP₁ but also approached the efficacy of silymarin. Mechanistically, AGP₂ produced 2.3- and 1.7-fold increases in nuclear Nrf2 and HO-1, respectively, and 67% and 55% reductions in p38 MAPK phosphorylation and Bax expression compared to the model group, surpassing the effects of both low- and high-dose AGP₁.

These findings identify AGP₂ as a promising low-molecular-weight polysaccharide candidate for liver protection and underscore the critical role of molecular weight in determining polysaccharide bioactivity. © 2026 Society of Chemical Industry.