Abstract:Polygala fallax Hemsl. is a geo-authentic medicinal and edible plant traditionally used by ethnic minority groups, but the material basis underlying its traditional hepatoprotective effects remains incompletely understood. This study aimed to investigate the protective effects and potential mechanisms of crude polysaccharides from Polygala fallax Hemsl.against acute alcoholic liver injury. PFP was prepared by water extraction and alcohol precipitation and the chemical composition was preliminarily characterized. A mouse model of acute alcoholic liver injury was established to evaluate its hepatoprotective activity, and an LPS-induced RAW264.7 cell model was further employed to investigate the underlying mechanisms. The results showed that the total sugar and protein contents of PFP were 48.33 wt.% and 2.85 wt.%, respectively. The uronic acid content was 30.02% (expressed as galacturonic acid equivalents). PMP-HPLC analysis revealed that PFP hydrolysates contained multiple monosaccharide components, including mannose, glucose, and galacturonic acid. Compared with the model group, the organ indices in the low- and high-dose PFP groups decreased by 4.00% and 7.29%, respectively. Serum alanine aminotransferase levels were decreased by 51.04% and 52.89%, serum lactate dehydrogenase levels were significantly decreased 43.46% and 56.45%, and hepatic interleukin-1β levels were reduced by 27.94% and 30.91%, respectively. In addition, serum aspartate aminotransferase was decreased by 16.16% in the high-dose PFP group. Histopathological examination further indicated that PFP alleviated pathological damage in liver and jejunal tissues. Furthermore, 16S rRNA sequencing revealed that PFP increased cecal microbiota diversity and modulated microbial community composition. Western blot analysis showed that high-dose PFP significantly restored mTOR expression and reduced Beclin-1 expression in cecal tissues. In LPS-induced RAW264.7 cells, PFP modulated the expression of autophagy-related proteins, including mTOR, Beclin-1, LC3-II, and p62. PFP partially ameliorated acute alcoholic liver injury in mice, and its mechanism may be associated with the regulation of gut microbiota and the autophagy signaling pathway. This study provides a theoretical basis for the development and application of Polygala fallax Hemsl. resources and related health products.