Nr4a3, also known as Neuron-derived Orphan Receptor 1 (NOR-1), is an orphan nuclear receptor with no identified natural ligands. Its biological activity can be mediated by interactions with specific small molecules and receptors. Nr4a3 is activated as an early stress factor, regulating processes like cell differentiation, apoptosis, metabolism, and homeostasis in various tissues and cells [3].

In vascular biology, Nr4a3-/-mice studies showed that Nr4a3 promotes vascular calcification. Its deficiency preserved the vascular smooth muscle cell contractile phenotype, inhibited osteoblast-related gene expression, and reduced calcium deposition. Nr4a3 enhanced glycolysis by binding to ALDOA and PFKL promoters, and histone lactylation promoted medial calcification [1].

In diabetes-induced atrial cardiomyopathy, Nr4a3-/-mice and over-expression models indicated that Nr4a3 protects against atrial remodeling by maintaining mitochondrial energy metabolism and reducing oxidative stress [2].

In thymic negative selection, Nr4a3-/-mice had an accumulation of self-reactive thymocytes, suggesting Nr4a3 is necessary to limit such accumulation [4].

In conclusion, Nr4a3 plays diverse and crucial roles in multiple biological processes and diseases. Gene-knockout mouse models have been instrumental in revealing its functions, such as in vascular calcification, diabetes-induced atrial cardiomyopathy, and thymic negative selection. Understanding Nr4a3 provides insights into disease mechanisms and potential therapeutic targets in these areas.