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Centering around the concept that metabolites from the gut commensals can exert metabolic health benefits along the gut–liver axis, we tested whether the cell-free global metabolome of probiotic bacteria can exert hepatoprotective benefits against H₂O₂-induced oxidative stress. Cell-free global metabolites of <i>Lactobacillus plantarum</i> (LPM) were isolated and untargeted metabolomics was performed. The free radical scavenging potentials of LPM were measured. The cytoprotective effects of LPM were tested on HepG2 cells. A total of 66 diverse metabolites were identified in LPM, among which saturated fatty acids, amino acids and dicarboxylic acids were highly enriched. LPM attenuated cell damage, lipid peroxidation and the levels of intracellular cytoprotective enzymes in H₂O₂-treated cells. LPM also attenuated H₂O₂-induced increased expressions of TNF-α and IL-6. However, the cytoprotective effects of LPM were diminished in cells that were pretreated with a pharmacological inhibitor of Nrf2. Our data collectively indicate that LPM can significantly attenuate oxidative damage to HepG2 cells. However, the cytoprotective effects of LPM likely depend on an Nrf2-dependent mechanism.