Nr4a1 regulates microglia overactivation-mediated neuroinflammation to ameliorate cognitive impairment in trigeminal neuralgia rats.

BACKGROUND: Cognitive impairment affects prognosis and quality of life in patients with trigeminal neuralgia (TN). Modulating hippocampal microglial activation is a promising approach for addressing TN-related cognitive deficits. Nuclear receptor subfamily 4 group A member 1 (Nr4a1) is involved in hippocampal-dependent cognition and microglial homeostasis. However, its role in trigeminal neuralgia-associated cognitive dysfunction remains unclear. We aimed to investigate the role of Nr4a1 in regulating neuroinflammation mediated by microglial hyperactivation, and to establish the relationship between the resulting synaptic plasticity impairment and cognitive dysfunction. METHODS: A TN rat model was established using chronic constriction injury of the distal infraorbital nerve. Cognitive function and hippocampal microglial activation were evaluated over time. Transcriptomic sequencing was performed to identify differentially expressed genes related to microglial activation. Nr4a1 was overexpressed in hippocampal microglia using adeno-associated virus and lentivirus in TN rats and BV2 cells, respectively. Multi-omics analyses, co-immunoprecipitation, and mass spectrometry were used for mechanistic assessments. RESULTS: Here, we observed that TN rats exhibited time-dependent cognitive impairment accompanied by excessive activation of hippocampal microglia and significant downregulation of Nr4a1 expression. Nr4a1 overexpression suppresses excessive activation of microglia and the neuroinflammation they mediate. These effects correlate with restored neuronal autophagy, enhanced synaptic plasticity, and improved cognitive function in TN rats. Mechanistically, we first revealed aberrant alterations in the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway through multi-omics sequencing. Furthermore, we identified Nr4a1 primarily targeting Akt2 among the Akt isoforms in the rat hippocampus. Restoring Nr4a1 expression reversed PI3K/Akt2 signaling downregulation in vivo and in vitro, whereas PI3K/Akt2 signaling pharmacological inhibition abrogated Nr4a1 overexpression-mediated benefits. CONCLUSION: Collectively, Nr4a1 may suppress excessive microglial activation by restoring the PI3K/Akt2 signaling pathway to alleviate neuroinflammation, thereby improving neuronal autophagy and synaptic plasticity. Our findings provide a deeper theoretical basis and molecular target for future TN-related cognitive impairment treatment. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10194-026-02293-3.