Gut-Liver Axis and Multi-Omics Analysis Reveal the Protective Effect and Mechanism of Luteolin against Dibutyl Phthalate Induced liver injury.

Dibutyl phthalate (DBP), a widely prevalent environmental endocrine disruptor, has raised significant public health concerns regarding its hepatotoxicity. Luteolin (Lut) possesses anti-inflammatory, antioxidant, and multi-target regulatory properties, but the mechanisms underlying its protection against DBP-induced liver injury have not been fully elucidated. Here, we employed a systematic strategy...to investigate these effects and their core mechanisms. Network analysis predicted the PI3K-AKT and TNF signaling pathways as core pathways involved in both DBP-induced hepatotoxicity and Lut intervention. Animal experiments confirmed that DBP exposure induced pathological liver damage, elevated serum ALT/AST levels, oxidative stress, and inflammatory imbalance in mice, all of which were dose-dependently ameliorated by Lut (especially at 50 mg/kg). Mechanistically, Lut inhibited DBP-induced hyperphosphorylation of the PI3K-AKT pathway, downregulated p-FOXO1 expression, and restored the phosphorylation balance of NF-κB/JNK in the TNF pathway, thereby re-establishing inflammatory homeostasis. Gut microbiota analysis revealed that Lut restored the abundance of beneficial bacteria disrupted by DBP and downregulated antibiotic resistance-related pathways. Hepatic metabolomics indicated that Lut regulated lipid metabolism, energy metabolism, and redox balance. Integrated multi-omics analysis confirmed the synergistic interaction between the gut microbiota and the hepatic metabolome, constructing a regulatory network of "DBP exposure → gut-liver axis dysregulation → liver injury → Lut intervention and repair." In conclusion, Lut exerts multi-dimensional hepatoprotective effects by targeting the PI3K-AKT/TNF signaling pathways and restoring gut microbiota-liver metabolic axis homeostasis, providing new insights for the prevention and protection of DBP-induced liver injury.