Nrf1, also known as Nuclear Factor Erythroid 2 Like 1 (Nfe2l1), is a stress-responsive transcription factor. It is involved in multiple crucial biological processes. Nrf1 participates in nuclear-mitochondrial interactions, regulates proteostasis and redox balance, and is central to cholesterol homeostasis. It also plays a role in the regulation of the ubiquitin-proteasome system [3,5,6]. Genetic models, such as KO/CKO mouse models, are valuable for studying its functions.

In KO mouse models, Nrf1 deficiency led to enhanced innate immunity, decreased viral load, and morbidity, suggesting its role in viruses-induced mitochondrial biogenesis to antagonize innate antiviral immunity [1]. In the context of heart regeneration, genetic deletion of Nrf1 prevented regenerating cardiomyocytes from activating the necessary transcriptional program, while its overexpression protected the adult mouse heart from ischemia/reperfusion injury [2]. In high-altitude cerebral edema, up-regulated Nrf1 in microglia under hypoxia accelerated pro-inflammatory factors and phagocytosis, contributing to the disease mechanism [4].

In conclusion, Nrf1 is essential for maintaining mitochondrial homeostasis, heart regeneration, and cholesterol balance. Its deficiency in KO/CKO mouse models has revealed its significance in antiviral immunity, heart injury protection, and high-altitude cerebral edema, providing insights into the underlying mechanisms of these biological processes and diseases.