Nr4a2, also known as Nurr1, is a nuclear receptor and transcription factor. It is widely expressed in the cell nuclei of the central nervous system and is a crucial regulator of dopaminergic (DA) neuronal differentiation, survival, and maintenance. It also regulates genes important for dopaminergic signals [6]. In addition, Nr4a2 has been associated with various physiological processes in the hippocampus, such as synaptic plasticity and memory formation, and may be involved in metabolic reprogramming in esophageal squamous cell carcinoma [2,3].

In a mouse model of non-alcoholic steatohepatitis (NASH), Nr4a2 overexpression promoted steatosis-to-NASH progression, while liver-specific Nr4a2 knockout mice were protected from diet-induced NASH, indicating its role in this disease process [4]. In the context of depression, chronic lipopolysaccharides (LPS) stress in mice led to depressive-like behaviors, and overexpression of Nr4a2 in the anterior cingulate cortex reversed these behaviors, suggesting its involvement in regulating depressive-like behaviors [1]. Also, in a mouse model of multiple sclerosis, neuron-specific deletion of Vgf, which is downstream of Nr4a2, ameliorated neurodegeneration, highlighting the role of the Nr4a2/VGF pathway in inflammation-induced neurodegeneration [5].

In conclusion, Nr4a2 plays essential roles in multiple biological processes, especially in the nervous system and in metabolic-related diseases. Gene knockout and conditional knockout mouse models have been instrumental in revealing its functions in diseases such as NASH, depression, and multiple sclerosis, providing insights into potential therapeutic targets for these conditions.