USF1 (upstream transcription factor 1) is a basic helix-loop-helix leucine zipper transcription factor that binds E-box sequences (5'-CACGTG-3') in gene promoters to regulate transcription by RNA polymerase II. USF1 functions as a metabolic regulator with broad involvement in lipid and glucose homeostasis, responding to cellular nutrient status and hypoxia. Mechanistically, USF1 activity is post-translationally regulated through phosphorylation; dephosphorylation of USF1 at S309 by PTP4A1 increases its transcriptional activity 1. USF1 transcriptionally activates target genes including SREBF2 (involved in cholesterol biosynthesis) 2, USP14 (a deubiquitinase) 3, ATG5 (autophagy regulator) 4, and A20/TNFAIP3 (NF-κB inhibitor) 1. USF1 protein stability is regulated by the USP5 deubiquitinase 4. USF1 dysfunction associates with metabolic and cardiovascular diseases. USF1 mutations cause familial combined hyperlipidemia type 1, and USF1 upregulation promotes atherosclerosis by driving endothelial-to-mesenchymal transformation through the USP14/NLRC5 axis 3. In cancer contexts, USF1 promotes immune evasion in colorectal cancer by directing cholesterol biosynthesis 2 and docetaxel resistance in lung cancer through autophagy induction 4. USF1 gene polymorphisms correlate with chemotherapy efficacy and toxicity in ovarian cancer 5. USF1 also regulates hematopoietic transcription factors relevant to leukemia pathogenesis 6.