Nr1d2, also known as REV-ERB-β, is a nuclear hormone receptor and an essential component of the circadian clock [5,6]. It is involved in regulating the expression of core clock proteins, thus playing a role in coordinating internal behavioural and physiological rhythms, as well as in metabolic processes [4,6]. It is also associated with pathways like Hippo and Notch [2]. Genetic models, such as knockout mouse models, are valuable for studying Nr1d2's functions.

Depleting Nr1d2 in hepatocellular carcinoma (HCC) cells decreased cell proliferation, migration, and invasion both in vitro and in vivo, with fewer metastatic nodules in the lungs. It also amplified epithelial marker expressions and decreased mesenchymal markers, indicating that Nr1d2 accelerates HCC progression via driving epithelial-to-mesenchymal transition [1]. In glioblastoma, silencing Nr1d2 inhibited cell proliferation and motility, and receptor tyrosine kinase AXL was identified as a new transcriptional target through which Nr1d2 regulated cell processes [3]. In melanoma, LINC01224 upregulated Nr1d2 expression by sponging miR-193a-5p, facilitating cell proliferation and inhibiting radiosensitivity [7]. In mouse sepsis-induced cardiomyopathy, mesenchymal stem cells alleviated the condition by downregulating Nr1d2 and its downstream target gene LCN2 [8].

In conclusion, Nr1d2 plays a significant role in regulating circadian rhythms and metabolism. Model-based research, especially gene knockout experiments, has revealed its involvement in promoting the progression of cancers like HCC, glioblastoma, and melanoma, as well as its role in sepsis-induced cardiomyopathy. Understanding Nr1d2's functions provides insights into disease mechanisms and potential therapeutic targets for these diseases.