RRN3 is a RNA polymerase I (Pol I)-specific transcription initiation factor essential for ribosomal RNA (rRNA) synthesis and cell growth. Functionally conserved between yeast and mammals 1, RRN3 forms competent pre-initiation complexes at rDNA promoters through both protein-protein interactions and direct DNA binding 2. Its HEAT repeat structure contains a serine patch whose phosphorylation represses Pol I transcription and regulates cell growth 3. Beyond canonical rRNA transcription, RRN3 functions dynamically in stress responses: under nutrient deprivation, phosphorylation at serine 199 diverts RRN3 from the nucleolus to regulate alternative polyadenylation of autophagy mRNAs, promoting cell survival 4. Clinically, elevated RRN3 associates with poor prognosis in pancreatic cancer, correlating with increased proliferation, invasion, and chemoresistance; RRN3 silencing sensitizes cancer cells to gemcitabine and paclitaxel 5. RRN3 upregulation also occurs during acute multiple sclerosis relapse 6. In zebrafish models, RRN3 heterozygosity affects ethanol sensitivity through altered neurochemical responses 7, suggesting RRN3 variants may influence drug metabolism and mental health outcomes in humans.