RABGEF1 (RAB guanine nucleotide exchange factor 1) primarily functions as a guanine nucleotide exchange factor that promotes the conversion of inactive RAB5-GDP to active RAB5-GTP, facilitating endosomal membrane trafficking and fusion 1. The protein forms complexes with RABEP1 to regulate endosome maturation and is essential for endocytic vesicle transport 2. Beyond its GEF activity, RABGEF1 also functions as an E3 ubiquitin ligase, promoting protein degradation through K63-linked ubiquitination and directing proteins to multivesicular bodies for lysosomal degradation 3. RABGEF1 plays crucial roles in maintaining tissue homeostasis by regulating intrinsic immune signaling pathways. In keratinocytes and intestinal epithelial cells, RABGEF1 dampens IL-1R/MYD88/NF-κB signaling to prevent excessive inflammation and maintain barrier function 4 5. Disease relevance includes its oncogenic role in glioblastoma, where it promotes cell proliferation and metastasis through AKT and ERK pathway activation 6, and its involvement in promoting TNF-induced necroptosis by targeting cIAP1 7. Clinically, reduced RABGEF1 expression is associated with allergic skin disorders and diabetic foot ulcers, making it a potential therapeutic target 4 8.