RFPL3 (ret finger protein like 3) is a RING-B30 domain-containing protein encoded on chromosome 22 that functions as a transcriptional regulator and E3 ubiquitin ligase with multiple roles in cancer and viral infection. RFPL3 contains characteristic RING finger, coiled-coil, and B30.2 domains that mediate protein-protein interactions 1. Primary function: RFPL3 acts as a transcription factor that binds to the hTERT promoter in lung cancer cells, activating human telomerase reverse transcriptase (hTERT) expression and telomerase activity 2. Additionally, RFPL3 stimulates HIV-1 preintegration complex integration activity through its N-terminal RING domain, likely via ubiquitin-mediated mechanisms 3. Mechanism: RFPL3 requires nuclear translocation via importin 13 (IPO13) recognition of its nuclear localization signal in the B30.2 domain 4. RFPL3 synergistically cooperates with CBP through CBP-induced acetylation to upregulate hTERT 5. EGF signaling through the MEK pathway upregulates RFPL3 expression, promoting hTERT activation 6. Disease relevance: RFPL3 overexpression correlates with poor prognosis in non-small cell lung cancer, lymph node metastasis, and reduced overall survival 2. Genome-wide association studies link RFPL3 variants to arousal dimension in psychiatric disorders 7. Clinical significance: RFPL3 represents a potential therapeutic target for NSCLC, with IPO13 inhibition and MEK pathway blockade as intervention strategies.