VPS35L is a core subunit of the Retriever complex, a multiprotein assembly essential for endosomal recycling of transmembrane cargo 1. As part of the Commander complex (composed of Retriever, the CCC complex containing COMMD1-10, CCDC22, CCDC93, and DENND10), VPS35L mediates the retromer-independent retrieval and recycling of over 120 cell surface proteins including integrins, lipoprotein receptors, and signaling receptors 12. Mechanistically, VPS35L associates with sorting nexin 17 (SNX17), which tethers cargo proteins to Retriever through a conserved interface between VPS35L and VPS26C subunits, facilitating endosome-to-plasma membrane transport 3. In hepatocytes, VPS35L specifically enables recycling of low-density lipoprotein receptor (LDLR) and LRP1 from endosomes to the cell surface, maintaining cholesterol homeostasis 4. VPS35L mutations cause Ritscher-Schinzel syndrome 3 (RTSCS3), characterized by craniofacial dysmorphism, cerebellar malformations, developmental delay, and notably hypercholesterolemia and intestinal lymphangiectasia 5. Additionally, VPS35L participates in viral trafficking, with evidence linking it to both human papillomavirus and porcine deltacoronavirus infection pathways 6. The severity of VPS35L-associated disease correlates with residual protein expression levels, suggesting a dose-dependent mechanism of pathogenesis.