USF3 is a basic helix-loop-helix leucine zipper transcription factor that functions as a negative regulator of epithelial-mesenchymal transition (EMT) 1. As a DNA-binding transcription activator, USF3 shows aversion toward methylated DNA sequences 2 and interacts with nucleosomes through well-defined binding modes 3. Mechanistically, USF3 enhances osteoblast differentiation and suppresses osteoclastogenesis by antagonistically interacting with anti-osteogenic transcription factor complexes at promoters of WNT16, RUNX2, and RANKL 4. A GWAS variant (c.3781C>A) in USF3's 3'-UTR is regulated by miR-345-5p, with the risk allele reducing osteogenic marker gene expression 5. Additionally, USF3 negatively regulates γδ T cell proliferation through mTOR signaling; USF3 knockout increases γδ T cell numbers and IFN-γ production, alleviating liver fibrosis 6. Clinically, USF3 alterations are associated with osteoporosis susceptibility 54 and thyroid carcinoma predisposition. Germline compound heterozygous deletions in USF3 are found in ~29% of Cowden syndrome patients and ~27% of papillary thyroid cancer cases, promoting EMT and glutamine-dependent survival 1. USF3 expression correlates with immune cell infiltration and cancer progression across urinary system malignancies 7.