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.

Sepsis remains a leading cause of mortality worldwide, driven by dysregulated inflammation and organ failure, with limited targeted therapies. Pyroptosis, mediated by gasdermin D (GSDMD), amplifies sepsis pathology through lipid peroxidation-dependent mechanisms, yet direct interventions are scarce. Leveraging the probiotic Escherichia coli Nissle 1917 (EcN) for gut-targeted delivery, we engineered EcN to secrete glutathione peroxidase 4 (GPX4), a pivotal antioxidant enzyme that curbs lipid peroxidation and pyroptosis. In an LPS-induced murine sepsis model, prophylactic oral EcN-GPX4 enhanced survival, mitigated multi-organ damage, and suppressed GSDMD cleavage across tissues. Dual mechanisms included: alleviation of oxidative stress and lipid peroxidation to block pyroptosis; and gut microbiota remodeling, enriching Ligilactobacillus murinus, which correlated with reduced LPS translocation and dampened arachidonic acid–linked pro-inflammatory metabolism. Via the gut–liver axis, EcN-GPX4 further attenuated hepatic TLR4/NF-κB signaling. This probiotic-based enzyme delivery offers a precise, microbiome-modulating strategy to interrupt pyroptotic amplification, with strong translational promise for sepsis management.