From Network Analysis to Functional Nutraceutical Protection: Pistacia lentiscus L. Mitigates DMBA-Induced Liver Damage Through AhR/ARNT Pathway Regulation.

Atmospheric pollution contributes to oxidative cellular damage and metabolic disorders due to hepatic metabolism of some toxins. In this study, we evaluated the in vitro antioxidant capacity of Pistacia lentiscus extract. Furthermore, the in vivo anti-inflammatory, antioxidant, and hepatoprotective effects were explored in DMBA-mice model. We also evaluated the systems-level characterization of gene networks associated with environmental response with genes regulated by the AhR/ARNT and HIF-2α/ARNT signaling pathways. Our results proved that P. lentiscus presented a rich source of fatty acids and secondary metabolites. In vitro, it demonstrated a strong free radical scavenging capacity with antioxidant effects. In vivo, DMBA exposure altered lipid profiles and CBCC with C-RP content, induced oxidative stress, and disrupted liver and kidney function. Cotreatment with P. lentiscus corrected plasma biochemical parameters, restored the C-RP activity and CBCC levels (C-RP: 0.9 µg/dL; WBC: 15.6 × 109/L; Mid: 0.22 × 109/L), reduced lipid peroxidation, and enhanced antioxidant enzyme activities (SOD, CAT, GPx; p < 0.05). Histological analysis confirmed the protective effects of P. lentiscus on liver tissue, preventing steatosis and cellular injury. Network analysis highlighted the central role of the AhR/ARNT complex and its molecular partners in coordinating xenobiotic metabolism and cellular adaptive responses, revealing a mechanistic basis for P. lentiscus as a promising anti-inflammatory and antioxidant dietary supplement with potential hepatoprotective effect.