EXPH5 (exophilin 5) is a Rab27b effector protein that plays a critical role in vesicular trafficking and exosome secretion. As a small GTPase binding protein, EXPH5 functions in multivesicular body (MVE) docking and trafficking, with silencing phenocopying Rab27b inhibition and reducing exosome secretion 1. In keratinocytes specifically, EXPH5 regulates extracellular vesicle secretion and coordinates focal adhesion dynamics to maintain cell-matrix adhesion and support keratinocyte migration 2. EXPH5 is involved in trafficking CD63+ vesicles containing extracellular matrix proteins to the plasma membrane, with loss-of-function mutations causing perinuclear vesicle accumulation 2. Beyond skin biology, EXPH5 is an ATM/ATR substrate involved in protein secretion and endosome dynamics 3, and emerges as a dysregulated biomarker in COPD and NAFLD-related hepatocellular carcinoma, with decreased expression correlating with disease progression 45. Biallelic EXPH5 mutations cause epidermolysis bullosa simplex 4, an autosomal recessive blistering disorder characterized by defective keratinocyte adhesion, early-onset skin fragility, and variable pigmentary alterations 26. The EXPH5 pathogenic mechanism involves compromised vesicle trafficking and reduced secretion of adhesion-supporting extracellular matrix proteins 7.