Nr2f6, also known as Ear-2, is an orphan nuclear receptor expressed in major human tissues and organs. It plays a crucial role in regulating various biological functions, gene expressions, and is involved in multiple pathways, including those related to metabolism, immune response, and cell differentiation. Genetic models, such as gene knockout (KO) mouse models, have been instrumental in understanding its functions [3].

In melanoma, genetic ablation of Nr2f6 in a mouse model led to a more effective response to PD-1 therapy. Nr2f6 loss in melanoma cells attenuated tumor development in immune-competent mice via increased abundance of effector and progenitor-exhausted CD8+ T cells, suggesting its role in regulating antitumor immunity [1].

In brown adipocyte differentiation, deletion of Nr2f6 in preadipocytes of mice (NR2F6-PKO) inhibited brown adipogenesis, caused hypertrophy of brown adipocytes, and impaired thermogenic function of brown adipose tissue (BAT), unveiling its importance in energy homeostasis [2].

In the context of non-alcoholic fatty liver disease (NAFLD), hepatic-specific suppression of Nr2f6 in mice improved obesity-associated hepatosteatosis, insulin resistance, and diet-induced non-alcoholic steatohepatitis (NASH), indicating its role in hepatic triglyceride (TG) homeostasis [4].

In skeletal muscle, Nr2f6 knockdown in mouse models upregulated genes related to muscle differentiation, metabolism, and contraction, while overexpression led to an atrophic and hypoplastic state with impaired force production, revealing its role in maintaining the balance between muscle contractile function and oxidative capacity [5].

In conclusion, Nr2f6 is essential for multiple biological processes. Model-based research, especially KO mouse models, has demonstrated its significance in diseases like cancer, metabolic disorders, and muscle-related conditions. Understanding Nr2f6 provides potential therapeutic targets for these disease areas.