Nr4a1, also known as nuclear receptor 4A1, is a ligand-activated transcription factor belonging to the NR4A subfamily of nuclear receptors. It is involved in multiple biological processes, including cell proliferation, apoptosis, and immune regulation, and is associated with pathways like the Hippo signaling pathway [3]. Its role has been investigated using various genetic models, such as gene-knockout (KO) mouse models, which have provided insights into its function in different physiological and pathological conditions.

In the context of intestinal fibrosis, Nr4a1-/-mice exposed to DSS showed increased colonic thickening and ECM content, and Nr4a1-/-myofibroblasts had enhanced TGF-β1-induced proliferation, suggesting that Nr4a1 can attenuate fibrotic processes in intestinal myofibroblasts [1]. Deleting Nr4a1 in CA1 pyramidal neurons of mice led to the impairment of cognition and excitatory synaptic function, indicating its role in age-dependent cognitive decline [2]. In the liver, NR4A1 forms a regulatory loop with YAP to coordinate Hippo signaling activity during liver regeneration and tumorigenesis [3]. In breast cancer cells, deletion of NR4A1 led to massive chromosomal instability and proliferative failure due to deregulated expression of its IEG target, FOS [4]. In melanoma, a PROTAC named NR-V04 that degrades NR4A1 can enhance anticancer immune responses [5]. In bone marrow mesenchymal stem cells, suppression of Nr4a1 by TGF-β1 impaired osteogenesis, while Nr4a1 overexpression promoted osteogenesis [6]. In the context of renal interstitial fibrosis, Nr4a1 promoted fibrosis potentially through activating p38 MAPK kinase in UUO mice and TGF-β1-treated HK-2 cells [7]. Platelet-specific NR4A1 deletion in mice accelerated thrombus formation and enhanced platelet activation, suggesting that NR4A1 negatively regulates these processes [8].

In conclusion, Nr4a1 is a crucial regulator in multiple biological processes. The use of KO/CKO mouse models has revealed its significance in diseases such as intestinal fibrosis, cognitive decline, liver diseases, cancer, bone regeneration disorders, renal fibrosis, and thrombosis-based cardiovascular diseases. Understanding Nr4a1's functions provides potential therapeutic targets for these disease areas.