AHR Activation Mediates Sodium Pentachlorophenol-Induced Mitochondrial Dysfunction and Cardiomyocyte Apoptosis through Oxidative Stress

Sodium pentachlorophenol (PCP-Na) is a persistent halogenated aromatic compound with poorly understood cardiotoxicity. This study investigated the underlying mechanisms using mouse models and HL-1 cardiomyocytes, integrating network toxicology, molecular docking, and targeted interventions with the AHR inhibitor CH223191, the antioxidant N-acetylcysteine (NAC), and the CYP1A1 inhibitor α-naphthoflavone (ANF). Findings demonstrate that PCP-Na promotes AHR nuclear translocation and dose-dependently activates the downstream target gene CYP1A1. This AHR/CYP1A1/ROS signaling axis triggers excessive oxidative stress, subsequently leading to mitochondrial dynamic imbalance, impaired ATP production, and cardiomyocyte apoptosis. By systematically elucidating these molecular pathways, this study highlights AHR as a direct target of PCP-Na and provides a critical theoretical basis for the safety assessment of agricultural and environmental matrices contaminated with persistent organic pollutants. These results offer novel insights into the protective potential of AHR/CYP1A1 inhibitors against halogenated contaminant-induced cardiac injury.