PLEKHA8 (pleckstrin homology domain containing A8) is a cargo transport protein essential for intracellular lipid trafficking and membrane organization. Its primary function involves mediating non-vesicular transport of glucosylceramide (GlcCer) from the trans-Golgi network to the plasma membrane, a process requiring binding of both phosphatidylinositol 4-phosphate and ARF1 1. PLEKHA8 also transports aquaporin-2 (AQP2) from the trans-Golgi network to phosphorylation sites and is required for primary cilium formation, potentially through raft lipid transport to the apical membrane 2. Mechanistically, PLEKHA8 operates through a unique GLTP-fold structural domain specific for glycosphingolipid binding and transfer 2. The protein plays a pivotal role in complex glycosphingolipid synthesis by channeling GlcCer to distinct glycosylation pathways 1. Clinically, PLEKHA8 has emerged as an oncogene implicated in both colorectal and hepatocellular carcinoma, where its dysregulated expression affects chemoresistance to 5-fluorouracil 3. Additionally, PLEKHA8 genetic variants have been associated with glucocorticoid sensitivity in acute lymphoblastic leukemia 4 and identified as potential functional variants for thyroid cancer susceptibility through m6A methylation regulation 5. These findings suggest PLEKHA8 as a potential therapeutic target in cancer treatment.