Short Chain Fatty Acids: A Novel Potential Target for Cadmium Hepatotoxicity.

Short chain fatty acids (SCFAs), the primary metabolites produced by gut microbiota, play an essential role in maintaining hepatic homeostasis. Recent studies have indicated that Cadmium (Cd) not only directly triggers oxidative stress and mitochondrial damage, but also indirectly exacerbates Cd-induced hepatotoxicity by depleting SCFAs, thereby compromising their protective effects on the liver. Cd alters gut microbiota composition by reducing the Firmicutes/Bacteroidetes ratio and depleting SCFAs-producing bacteria such as Lachnospiraceae and Ruminococcaceae, thereby decreasing SCFAs production. It induces intestinal epithelial necrosis and downregulates tight junction proteins (occludin, claudin-1, and ZO-1), which impairs SCFAs absorption, compromises intestinal barrier function, and promotes the translocation of endotoxins to the liver via the gut-liver axis. Cd further disrupts SCFAs metabolism and promotes lipid accumulation by suppressing β-oxidation related genes and proteins, thereby synergistically exacerbating hepatic damage. We also highlight the potential of exogenous SCFAs supplementation to alleviate Cd toxicity by restoring microbial balance, elevating SCFAs levels, and enhancing barrier integrity. These insights offer a novel perspective and strategic basis for dietary interventions in preventing and treating heavy metal related liver diseases.