Abstract:Polysaccharides of Tremella fuciformis (TFPS) represent the fundamental and primary bioactive components extracted from the traditional medicinal and edible fungus?Tremella fuciformis. In order to systematically and thoroughly explore the potential detoxification effects and the intricate underlying mechanisms of TFPS against cadmium (Cd)-induced hepatic injury, a total of 40 healthy male ICR mice were randomly allocated into four distinct experimental groups, namely the normal control group, the Cd-exposure model group, the TFPS-alone intervention group, and the TFPS combined with Cd intervention group.Analysis conducted through the highly sensitive technique of inductively coupled plasma mass spectrometry (ICP-MS) revealed that systemic exposure to cadmium (Cd) led to a remarkably significant and abnormal sequestration of Cd within multiple vital organs, including the liver, kidneys, spleen, lungs, and heart (p<0.001). Simultaneously, this excessive accumulation was shown to profoundly disrupt the delicate internal physiological homeostasis of critical essential trace elements—namely zinc (Zn), manganese (Mn), copper (Cu), and selenium (Se)—within the hepatic tissues.Following the therapeutic administration of TFPS, the excessive cadmium (Cd) concentrations within the various vital visceral organs were significantly and markedly diminished. Simultaneously, this treatment effectively and efficiently restored the previously disrupted homeostatic levels and physiological equilibrium of the aforementioned essential trace elements toward their baseline normal states.Furthermore, 16S Rrna（16S rRNA gene sequencing） sequencing indicated that TFPS remodeled the gut microbiota dysbiosis induced by Cd exposure, characterized by the enrichment of potential beneficial bacteria (e.g., Faecalibaculum and Akkermansia) and the reduction of harmful bacteria (e.g., Desulfovibrio), thereby alleviating heavy metal-induced damage. The analytical outcomes obtained from the high-resolution untargeted metabolomics investigation demonstrated that the administration of TFPS exerted a significant and profound impact on a wide spectrum of metabolites intimately associated with histidine, glutamine, various lipid species, and bile acid derivatives. Furthermore, TFPS treatment was found to remarkably modulate the complex small-molecule metabolic landscapes within the hepatic tissues, effectively regulating the physiological levels of diverse metabolites intrinsically involved in critical biochemical processes, such as amino acid metabolism, lipid homeostatic regulation, and the intricate biosynthetic pathways of bile acids. Integrated analysis of 16S rRNA and metabolic pathways suggested that TFPS exerts its systematic detoxifying effects via the "microbiota-metabolism-elemental homeostasis" network. This study is the first to systematically reveal the integrated mechanisms of TFPS in alleviating Cd toxicity through three dimensions: multi-organ elemental distribution, gut microbiota remodeling, and hepatic metabolic regulation. These findings provide a solid scientific basis for the development of functional foods or additives for heavy metal detoxification.