Theabrownin Alleviates PCB138-Induced Intestinal Damage by Suppressing Oxidative Stress-Mediated Intestinal Epithelial Cell Necroptosis

2,2',3,4,4',5'-Hexachlorobiphenyl (PCB138) is a persistent organic pollutant with potential intestinal toxicity. Theabrownin (TB) can improve intestinal injury, but its protective effect against PCB138 remains unclear. This study found that 48-week PCB138 exposure induced ileal damage, inflammation, oxidative stress, and necroptosis in mice, which were mitigated by TB intervention. TB alleviated PCB138-induced intestinal damage by suppressing oxidative-stress-mediated intestinal epithelial cell necroptosis. Mechanistically, both TB and N-acetylcysteine (NAC) suppressed PCB138-triggered ROS and subsequent RIPK1/RIPK3/MLKL phosphorylation. The additive effect of NAC combined with necrostatin-1 confirmed ROS as the upstream trigger and RIPK1 as the downstream executor. TB acts similar to NAC, establishing that it prevents necroptosis by scavenging upstream ROS. This study revealed a new mechanism of PCB138-induced intestinal toxicity and identified TB as a potential protective agent against environmentally pollutant-triggered intestinal inflammation.