Dietary Tamarixetin Alleviates Copper Overload-Induced Hepatotoxicity via Copper Chelation, Cuproptosis Inhibition, and Gut-Liver Axis Modulation: A Study on Flavonoid-Metal Interactions

Abstract Excessive dietary copper is a nutritional toxicant that disrupts homeostasis and provokes liver injury; yet the role of cuproptosis (copper-dependent cell death) is not fully defined. Tamarixetin (TAM), a food-derived flavonoid with copper-chelating and antioxidant capacity, was evaluated as a protective bioactive. We demonstrate that copper overload drives hepatotoxicity predominantly through cuproptosis. TAM lowered labile copper and activated the nuclear receptor NR1I2, thereby upregulating lipoic acid synthase (LIAS) to inhibit cuproptosis and restore tricarboxylic acid cycle function. NR1I2 overexpression phenocopied TAM-mediated protection, confirming the NR1I2–LIAS axis. TAM also reshaped the gut microbiota, enriching Lactobacillus and, via the gut–liver axis, suppressing NF-κB–mediated hepatic inflammation. Overall, these findings reveal a flavonoid–metal interaction-based defense mechanism and support TAM as a functional ingredient or nutraceutical to mitigate high dietary copper exposure.