DENND4C encodes a guanine nucleotide exchange factor (GEF) that activates RAB10 by promoting GDP-to-GTP exchange, converting RAB10 to its active form 1. This activation is essential for insulin-stimulated GLUT4 glucose transporter translocation to the plasma membrane in adipocytes and muscle cells, a critical mechanism for insulin-mediated glucose uptake 1. DENND4C localizes to isolated GLUT4 vesicles and functions within the endosomal retrieval sub-domain as part of a Retromer-centered hub that integrates cargo recycling with RAB GTPase regulation 2. Beyond glucose metabolism, circular RNA derived from DENND4C (circDENND4C) exhibits regulatory functions in disease contexts. CircDENND4C protects against acute kidney injury by inhibiting pyroptosis through a miR-138-5p/FOXO3a axis in exosomes from urine-derived stem cells 3. In cancer, circDENND4C promotes breast cancer progression via the miR-26a-5p/HSPA8 axis and facilitates colorectal cancer proliferation and glycolysis through the miR-760/GLUT1 axis 4 5. CircDENND4C also regulates blood-tumor barrier permeability through a miR-577-dependent mechanism, potentially enhancing drug delivery 6. A DENND4C genetic variant is associated with both type 2 diabetes susceptibility and eosinophil count variation 1 7, and DENND4C expression is reduced in infertile males with nonobstructive azoospermia 8.