CD44 and related hyaluronic acid receptors (CD44)

CD44 and related hyaluronic acid (HA) receptors, including RHAMM (CD168), LYVE-1, and HARE (Stabilin-2), constitute a group of cell-surface proteins that mediate interactions with the extracellular matrix component hyaluronan [2, 11, 12]. CD44 is the most prominent member, acting as a multifunctional transmembrane glycoprotein that regulates cell adhesion, migration, and survival signaling through pathways such as PI3K/Akt and MAPK [3, 15, 17]. These receptors are critical in physiological processes like lymphocyte homing, wound healing, and tissue remodeling, but are frequently hijacked in pathological states [7, 18]. In oncology, CD44 is a hallmark of cancer stem cells and is strongly associated with tumor metastasis, epithelial-mesenchymal transition, and resistance to chemotherapy [3, 13, 23]. Therapeutic targeting of this axis involves monoclonal antibodies, antibody-drug conjugates, and HA-conjugated nanomedicines designed to exploit the high expression of these receptors in diseased tissues [3, 4, 10]. However, challenges such as ubiquitous expression in normal tissues and severe dermatological toxicities have complicated clinical development [14, 17].

Competitive inhibition of ligand binding, targeted drug delivery via receptor-mediated endocytosis, ligand depletion by hyaluronidase, and inhibition of hyaluronan synthesis.