NRF1 (Nuclear Respiratory Factor 1) is a multifunctional transcription factor that plays critical roles in cellular metabolism, stress response, and disease pathogenesis. Primarily, NRF1 activates transcription of genes involved in mitochondrial biogenesis, proteasome function, and cellular respiration 12. The protein exhibits position-dependent transcriptional activity, functioning as either an activator or repressor depending on its precise location relative to transcription start sites 3. NRF1's mechanism involves cooperative interactions with other transcription factors like E2F4 and MYC to regulate common target genes across multiple cellular pathways 4. Post-translational regulation occurs through ubiquitination pathways that impair its activation, involving SCFFBS2-ARIH1-mediated atypical ubiquitin chain formation 5. In disease contexts, NRF1 demonstrates dual roles: it promotes heart regeneration through proteostasis and redox balance regulation 6 and enhances CAR-NK cell therapeutic efficacy via c-Myc/NRF1 activation 7. However, NRF1 also contributes to cellular senescence by driving innate immune responses through the ATM-NRF1-TBK1/IRF3 axis 8. In Alzheimer's disease, impaired NRF1 nuclear localization prevents compensatory proteasome upregulation, contributing to proteostasis failure 2. These findings establish NRF1 as a key regulator linking metabolic control, stress responses, and disease progression.