Acute pancreatitis (AP) has a high mortality, involving oxidative stress and mitochondrial damage. Nuclear receptor subfamily 4 group A member 3 (Nr4a3) and BTG anti-proliferation factor 2 (Btg2) have a close connection with mitochondrial damage. Here, we found that Nr4a3 expression was upregulated in pancreatic tissues of AP mice induced by cerulein. To elucidate Nr4a3's role, we injected adeno-associated virus 9 (AAV9) carrying Nr4a3-targeting short hairpin RNA into the pancreatic duct. This intervention reduced pancreatic edema, inflammatory infiltration, and acinar cell necrosis by suppressing pancreatic enzyme activation. Moreover, Nr4a3 knockdown improved mitochondrial function in pancreatic acinar cells, evidenced by increased mitochondrial membrane potential, enhanced ATP production, and decreased superoxide levels. It also inhibited cell apoptosis by suppressing the activation of the caspase pathway. In vitro, Nr4a3 knockdown in CCK-treated pancreatic acinar cells decreased oxidative stress, mitigated mitochondrial damage, and suppressed apoptosis, while Nr4a3 overexpression exacerbated cell injury. Further investigation identified Btg2 as a downstream target of Nr4a3. Btg2 expression was elevated in pancreatic acinar cells of AP mice, and siRNA-mediated Btg2 knockdown alleviated CCK-induced cell injury. Mechanistically, Nr4a3 promoted Btg2 transcription, thereby promoting mitochondrial damage in pancreatic acinar cells and leading to cell apoptosis. Btg2 overexpression reversed the protective effects of Nr4a3 knockdown. Overall, our findings demonstrate that downregulation of Nr4a3 exerts anti-AP effects by regulating Btg2, providing potential therapeutic targets for AP.
T-2 toxin is a widely distributed environmental mycotoxin that poses severe neurotoxic risks to humans and animals. Neuroinflammatory responses constitute a key mechanism underlying the neurotoxicity of T-2 toxin. However, its molecular mechanisms for inducing inflammatory responses in the nervous system remain incompletely understood. This study investigated the role of B-cell translocation gene 2 (BTG2) in T-2 toxin-induced microglial activation and evaluated the neuroprotective potential of resveratrol (Res). In vivo experiments demonstrated that exposure to T-2 toxin resulted in spatial learning, memory impairments and locomotor deficits in mice. These behavioral phenotypes were accompanied by neuroinflammation in the hippocampus and cerebral cortex, characterized by microglial activation and the upregulation of BTG2. Res pre-treatment effectively reversed these neurobehavioral deficits and suppressed the neuroinflammatory response. Mechanistic analyses revealed that Res considerably alleviated T-2 toxin-induced TLR4/MyD88/NF-κB pathway activation. In vitro studies using BV-2 microglial cells confirmed these findings. Notably, siRNA-mediated knockdown of BTG2 also abolished TLR4 pathway activation and subsequent cytokine expression induced by T-2 toxin, establishing BTG2 as a critical upstream regulator. Furthermore, RNA sequencing systematically verified that BTG2 regulates the immune response network, specifically targeting the TLR4 cascades. Collectively, these findings provide novel evidence that Res may target the BTG2-regulated TLR4/MyD88/NF-κB signal pathway to exert neuroprotection, providing a promising intervention option for reducing the environmental and health hazards associated with exposure to T-2 toxin
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