Molecular weight‐dependent hepatoprotection of American ginseng polysaccharides

Abstract BACKGROUND 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. RESULTS Two polysaccharide fractions, AGP 1 (>100 kDa) and AGP 2 (<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 CCl 4 ‐induced acute liver injury mouse model. Both fractions dose‐dependently reversed these alterations, with AGP 2 consistently outperforming AGP 1 at equivalent doses. Compared with the model group, high‐dose AGP 2 (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 AGP 1 but also approached the efficacy of silymarin. Mechanistically, AGP 2 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 AGP 1 . CONCLUSION These findings identify AGP 2 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.