Astaxanthin Alleviates Lead‐Induced Toxicity by Restoring Hepatic and Gut–Liver Axis Homeostasis Through Multidimensional Metabolic and Antioxidative Pathways

Lead (Pb) poisoning is a major public health concern of environmental origin in the world. It is essential to develop effective ways such as utilizing natural products as therapeutic agents for prevention and therapy of Pb-induced diseases. This study explores the effects and underlying mechanisms of astaxanthin (ATX), a natural compound with potent antioxidant properties, in alleviating Pb-induced toxicity in model mice. Supplementation with ATX significantly ameliorated lead-induced physiological and biochemical disruptions, including weight loss, hepatic and renal damage, and metabolic imbalances. Metabolomic and transcriptomic analyses revealed that ATX played a positive role in improving redox homeostasis, regulating lipid, amino acid, and nucleotide metabolism, and activating critical pathways such as Nrf2/ARE, PPAR, and S1P, thereby enhancing the antioxidative, anti-inflammatory, and detoxification capacities of the mice. ATX supplementation also modulated mouse gut microbiota by promoting beneficial bacterial populations, suppressing harmful strains, and increasing short-chain fatty acid production, thereby effectively restoring gut-liver axis balance. These findings demonstrate that ATX possesses comprehensive activities against lead toxicity via multi-dimensional regulatory mechanisms, highlighting ATX as a promising therapeutic agent for heavy metal poisoning. Further research is warranted to validate the clinical applications of ATX and evaluate its long-term safety.