Effect of Lachnum YM156 Polyphenol on STAT3/COX-2 Signal Pathway and Gut Microbiota in Mice with N-Nitrosodiethylamine-Induced Hepatic Injury

Research background. Global food security faces escalating threats from chemical contaminants, with N-nitrosodiethylamine (NDEA) emerging as a potent hepatotoxicant of significant concern. NDEA-induced hepatic injury orchestrates a pathological triad through: (i) reactive oxygen species-mediated oxidative cascades, (ii) nuclear factor κB-driven inflammatory amplification, and (iii) Although natural polyphenols demonstrate established protective efficacy, fungal-derived variants remain pharmacologically enigmatic, particularly regarding their pathway-specific regulation and microbiota modulation. We comprehensively investigated the therapeutic capacity of Lachnum polyphenols for hepatoprotection. Experimental approach. The hepatoprotective and microbiota-modulating efficacy of extracellular polyphenol from Lachnum YM156 (LSP156) was evaluated in an NDEA-induced mouse model. Sixty male ICR mice were randomised into six experimental groups receiving 28-day oral LSP156 treatment. Body mass measurements, hepatosomatic indices, systemic oxidative stress biomarkers (superoxide dismutase [SOD] and malondialdehyde) and pro-inflammatory cytokines (interleukin [IL]-6 and tumour necrosis factor [TNF]-α) were assessed. Hepatic histopathology was analysed by haemotoxylin and eosin staining, whereas immunoblotting with chemiluminescence detection assessed the STAT3/COX-2 pathway activation. Gut microbiota composition was profiled through 16S rRNA sequencing. Results and conclusions. After 28-day oral administration (50-100 mg/kg/day), LSP156 significantly improved somatic growth parameters (body mass gain) and organ indices in NDEA-induced mice. LSP156 increased the activities of SOD and catalase, and levels of glutathione, greatly reduced the liver function markers alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin, and improved liver cell damage in tissue samples compared to model controls. LSP156 halted the activation of STAT3 and reduced TLR4 levels, which lowered cyclooxygenase protein levels to protect the liver from damage. LSP156 enhanced the digestion and absorption of carbohydrates and proteins, as well as the biosynthesis of terpenoids such as ubiquinone in mice, by rectifying intestinal flora imbalances, modifying the flora structure, and demonstrating a strong correlation between Bacteroidales and Lactobacillales with the reduction of TNF-α and IL-6. The LSP156 demonstrated dose-dependent therapeutic efficacy in attenuating oxidative stress, hepatocyte impairment, and systemic inflammation. Novelty and scientific contribution. Fungal polyphenol LSP156 maintains gut bacteria balanced by managing inflammation and oxidation together. These findings outline a new approach for designing drugs targeting multiple factors in complex metabolic disorders.