Cd63, a member of the transmembrane-4-superfamily of tetraspanin proteins, is a highly N-glycosylated type III lysosomal membrane protein. It plays crucial roles in multiple biological processes. Cd63 is involved in extracellular vesicle (EV)-related functions, such as endosomal cargo sorting and EV secretion. It also participates in lipid-sorting within endosomes and is associated with iron-regulated ferritin secretion. Additionally, its expression is linked to cancer malignancy, with implications for cancer detection and prognosis [3,4,5].

Studies have shown that Cd63 sorts cholesterol into endosomes for storage and distribution via exosomes. In the absence of Cd63, cholesterol retrieval from endosomes occurs through actin-dependent vesicular transport, indicating Cd63's role in the balance of endomembrane budding [1]. Also, Cd63 expression is regulated by iron via the IRE-IRP system, and under iron loading, it is important for the transfer of intracellular ferritin to Cd63 + EVs for secretion [2]. In the context of cancer, CD63 + cancer-associated fibroblasts can confer CDK4/6 inhibitor resistance to breast cancer cells through exosomal miR-20 [6].

In summary, Cd63 is essential for endosomal lipid-sorting, EV-related functions including ferritin secretion, and has significant implications in cancer-related processes. Research using gene-knockout models has revealed its role in cholesterol handling, iron-regulated ferritin secretion, and cancer-associated drug resistance, providing insights into potential therapeutic targets for diseases such as cancer.