Cd44, a non-kinase cell surface transmembrane glycoprotein, is widely studied for its roles in multiple biological processes. It has a significant impact on cell proliferation, adhesion, migration, angiogenesis, inflammation, and cytoskeleton rearrangement in normal and cancer cells [1,2,3]. It is also involved in metabolism, especially insulin resistance in obesity and diabetes [2]. Cd44 regularly undergoes alternative splicing, resulting in the standard (CD44s) and variant (CD44v) isoforms, which interact with ligands like hyaluronic acid (HA), osteopontin (OPN), and matrix metalloproteinases (MMPs), driving numerous cancer-associated signaling pathways [1,3].

In the context of cancer, cells overexpressing CD44 possess cancer stem cell (CSC) traits such as self-renewal, epithelial-mesenchymal transition (EMT) capability, and resistance to chemo-and radiotherapy [1]. The hyaluronan-CD44 axis is crucial for CSC functions, including stemness properties and drug resistance through induction of the EMT program, oxidative stress resistance, secretion of extracellular vesicles/exosomes, and epigenetic control [5]. In triple-negative breast cancer, the platelet endothelial aggregation receptor 1 (PEAR1) protects CD44 from endocytosis-mediated degradation, enhancing cleavage of the CD44 intracellular domain (CD44-ICD), and promoting metastasis [6]. In the vascular endothelium, CD44 negatively regulates autophagy by reducing PIK3R4 and PIK3C3 levels and disrupting STAT3-dependent PtdIns3K complexes, and its increase with age induces autophagy decline and ageing phenotypes [4].

In conclusion, Cd44 is a multifunctional molecule with key roles in cancer progression, metabolism, and vascular endothelial ageing. In cancer, it contributes to tumorigenic mechanisms such as cell proliferation, metastasis, and stemness. In metabolism, it is involved in insulin resistance. In the vascular endothelium, it links autophagy decline and ageing. Studies, including those using potential Cd44-related KO/CKO mouse models (not explicitly detailed in references but inferred from research context), help to further understand its functions in these disease-related processes.