3,4-hydroxyphenyl lactic acid from Lactiplantibacillus plantarum prevents alcoholic liver injury in mice
Alcoholic liver disease (ALD) is a major health burden linked to oxidative stress, gut dysbiosis, and disrupted hepatic metabolism. While Lactiplantibacillus plantarum (L. plantarum) has shown potential in alleviating ALD, the specific mechanisms and bioactive components remain unclear. This study investigated the hepatoprotective effects of L. plantarum fermentation liquid (PFL) and its key metabolite, 3,4-hydroxyphenyl lactic acid (HPLA), against alcohol-induced liver injury. Using acute and chronic alcohol intoxication mouse models, we demonstrated that PFL significantly reduced mortality, attenuated hepatocyte damage, and restored alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) activities. UHPLC-QTOF-MS/MS analysis identified HPLA as the primary active component in PFL, exhibiting potent antioxidant properties. In vitro and in vivo experiments revealed that HPLA mitigated oxidative stress by enhancing superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, reducing malondialdehyde (MDA) levels, and suppressing lipid accumulation. Mechanistically, network pharmacology and molecular validation highlighted that HPLA alleviated hepatic injury by modulating the EGFR/PPAR- signaling axis, thereby counteracting alcohol-induced oxidative stress and lipid metabolism disorders. These findings elucidate a novel "gut-liver" axis mechanism mediated by HPLA, offering a theoretical foundation for the clinical application of L. plantarum and its metabolites in ALD management. ImportanceNumerous animal studies and clinical trials have demonstrated the effectiveness of probiotics in treating alcoholic liver disease. In this study, we primarily created a mouse model for both acute and chronic alcoholism and discovered that Lactiplantibacillus plantarum fermentation solution significantly decreased the inflammatory response and oxidative stress caused by alcohol. Its key metabolite, 3,4-hydroxyphenyl lactic acid (HPLA), exhibited strong antioxidant properties, helping to reduce oxidative stress by preventing lipid accumulation. This research offers insights into how probiotic interventions can mitigate alcoholic liver damage, enhancing our understanding of the protective effects of Lactiplantibacillus plantarum and emphasizing the potential of its metabolite, HPLA, as a targeted treatment for alcoholic liver disease.