RNF217 is an E3 ubiquitin ligase belonging to the RBR (RING-IBR-RING) family that catalyzes ubiquitin transfer to substrate proteins 1. As an RBR E3 ligase, RNF217 contains conserved transmembrane and GXXXG motifs critical for self-association and membrane localization, regulatory mechanisms shared across the RBR family 2. Primary function involves iron homeostasis regulation through ferroportin/SLC40A1 ubiquitination and degradation. Beyond iron metabolism, RNF217 regulates ferroptosis resistance in esophageal squamous cell carcinoma by promoting KEAP1 ubiquitination and degradation, thereby stabilizing NRF2 and enhancing antioxidant signaling in a feedback loop 3. RNF217 interacts with the anti-apoptotic protein HAX1 via its C-terminal RING domain, potentially contributing to leukemia development 4. The gene shows regulated splicing during B cell development and is implicated in multiple cancers, with expression significantly correlating to clinicopathological parameters and prognosis in lung adenocarcinoma 1. Additionally, the upstream long non-coding RNA RNF217-AS1 encodes bioactive peptides that suppress gastric cancer tumorigenesis and macrophage recruitment 5, while STL regulates RNF217 expression to suppress angiogenesis in dental pulp stem cells 6. RNF217 represents a multifunctional ubiquitin ligase with disease relevance across cancer types and metabolic disorders.