RHBDF1 is a multi-transmembrane endoplasmic reticulum protein that functions as a critical regulator of EGFR signaling and cellular stress responses, with significant oncogenic properties across multiple cancer types. **Primary Function:** RHBDF1 acts as a non-catalytic regulator of ADAM17 protease activity 1, facilitating the shedding and secretion of EGFR ligands, particularly TGFα 2. It does not possess protease activity itself but rather modulates protein trafficking and processing events essential for growth factor signaling. **Mechanism:** RHBDF1 operates through multiple pathways: (1) promoting clathrin-coated vesicle-dependent membrane trafficking of pro-TGFα 2; (2) stabilizing HIF1α by preventing RACK1-mediated degradation in hypoxic conditions 3; (3) upregulating PERK expression via the JNK/FoxO3 axis to support the unfolded protein response 4; and (4) protecting glycolytic enzymes from TRIM32-mediated degradation 1. **Disease Relevance:** RHBDF1 is elevated in breast, pancreatic, and melanoma cancers 561. Alternative splicing generates an inhibitory variant (RHX6) that suppresses RHBDF1 activity and is lost in cancer cells 5. RHBDF1 was identified as a glioblastoma-associated gene through proteome-wide association studies 7. **Clinical Significance:** RHBDF1 inhibition suppresses tumor growth, metastasis, and enhances immunotherapy efficacy in melanoma 1, positioning RHBDF1 as a potential therapeutic target for multiple malignancies.