RNF139 is a membrane-bound E3 ubiquitin ligase that functions as a multifaceted regulator of cellular homeostasis and tumor suppression. Primarily, RNF139 acts as a negative regulator of cell proliferation through G2/M arrest and apoptosis induction 1. In lipid metabolism, RNF139 plays a central role in sterol-accelerated degradation of HMGCR by binding to INSIG1/INSIG2 at the ER membrane and facilitating ubiquitination through interaction with AUP1 and UBE2G2 23. RNF139 also modulates SREBP processing by hindering SREBP-SCAP complex translocation, thereby regulating cholesterol homeostasis 4. Additionally, RNF139 is required for MHC class I ubiquitination during viral infection 5 and functions within the ERAD pathway as a sensor of membrane lipid composition, with its activity modulated by the E2 enzyme UBE2J2 in response to lipid packing density 6. Clinically, RNF139 exhibits tumor-suppressive properties across multiple cancer types. In glioma, RNF139 downregulation promotes aggressive behaviors, with restoration of RNF139 expression inhibiting cell proliferation, migration, and invasion through PI3K/AKT pathway suppression 1. Similar tumor-suppressive effects are documented in tongue cancer, where RNF139 overexpression decreases cell viability and xenograft tumorigenicity 7. In bladder cancer, NR4A3-induced upregulation of RNF139 promotes ATF6 ubiquitination and degradation, enhancing therapeutic efficacy 8. Conversely, RNF139 upregulation in Abraxane-resistant lung cancer cells suggests context-dependent roles in drug resistance 9.