RNF121 is a Golgi-localized E3 ubiquitin ligase that regulates protein stability and signaling through ubiquitin-dependent degradation pathways 1. While the UniProt database suggests involvement in endoplasmic reticulum-associated degradation (ERAD), human RNF121 predominantly localizes to the Golgi apparatus rather than the ER 1, where it functions as a quality control factor 2. The protein's RING domain is essential for its catalytic activity 1. Mechanistically, RNF121 regulates multiple cellular processes through distinct substrates. It directly binds and stabilizes MYCN protein in neuroblastoma, enhancing oncogenic signaling 3, while promoting ubiquitination of VEGFR-2 to restrict its cell surface expression and angiogenic signaling 4. RNF121 facilitates polyubiquitination of SARS-CoV-2 ORF7a to promote NF-κB activation 5 and regulates AAV genome transcription through a network involving VCP and DNA damage response elements 6. Disease relevance is substantial: high RNF121 expression associates with poor prognosis in MYCN-amplified neuroblastoma and laryngeal cancer 3, while RNF121 acts as a tumor suppressor in renal cell carcinoma 7. In SARS-CoV-2 infection, RNF121-mediated ubiquitination contributes to excessive NF-κB activation and inflammatory cytokine production 5. RNF121 depletion enhances cisplatin sensitivity in non-small-cell lung cancer 8, suggesting therapeutic potential.