RAB5IF is a multifunctional mitochondrial protein with critical roles in both protein biogenesis and mitochondrial respiration. As a component of the multi-pass translocon (MPT) complex at the endoplasmic reticulum, RAB5IF mediates insertion of multi-pass membrane proteins into lipid bilayers by occluding the SEC61 complex lateral gate to promote insertion of subsequent transmembrane regions 1. Beyond membrane protein biogenesis, RAB5IF functions as an assembly factor for mitochondrial respiratory complexes and supports mitochondrial respiration and ribosome biogenesis 2. Rab5IF operates through a RAB5IF-SUMO2-Gαi1/3 signaling axis essential for retinal angiogenesis, with SUMO2 serving as a critical downstream protein that regulates VEGF signaling 3. Pathogenic variants in RAB5IF cause craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-2 (CFSMR2), likely due to impaired ER-mitochondria interactions 2, 4. Additionally, RAB5IF has been implicated as a potential oncogenic factor, with elevated expression in hepatocellular carcinoma and non-small cell lung cancer associated with poor prognosis, where it promotes tumor proliferation via the AKT-mTOR pathway 5, 6. RAB5IF may serve as a diagnostic biomarker in steroid-induced osteonecrosis of the femoral head 7.