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CD44

CD44

Overview

CD44 is a multifunctional transmembrane glycoprotein and cell surface receptor broadly expressed across mammalian tissues, where it plays central roles in cell adhesion, migration, proliferation, and survival. It functions primarily as a receptor for hyaluronic acid (hyaluronan), a major component of the extracellular matrix, as well as for other ligands including osteopontin, collagens, and matrix metalloproteinases. Through these interactions, CD44 mediates intracellular signaling cascades — notably the PI3K/Akt and JAK2/STAT3 pathways — that govern fundamental cellular processes including epithelial-to-mesenchymal transition (EMT), stem cell maintenance, and immune modulation. CD44 exists in multiple isoforms generated by alternative splicing of up to 10 variant exons, allowing context-dependent expression across cell types and disease states.

In oncology, CD44 is widely recognized as a cancer stem cell (CSC) marker, often co-expressed with other stemness-associated proteins such as epithelial cell adhesion molecule (EPCAM). Its overexpression has been documented across a broad spectrum of malignancies — including liver cancer, colorectal cancer, bladder cancer, breast cancer, and prostate cancer, among others — where it is associated with tumor aggressiveness, therapy resistance, and metastatic potential. Because of its consistent surface overexpression on tumor cells and immunological relevance, CD44 has also emerged as a high-value target for receptor-mediated drug delivery systems, particularly those utilizing hyaluronic acid as a targeting ligand.

Focus of Latest Publications

Recent publications have continued to examine CD44 as a cancer-associated target, particularly in the context of tumor stemness, invasion, and the tumor microenvironment. In triple-negative breast cancer, CD44 was discussed as a key cell-surface receptor for extracellular matrix components and as a biomarker associated with breast cancer stem cells, with one study evaluating adapalene as an inhibitor of CD44 activity. In hepatocellular carcinoma, CD44 was linked to cancer stemness through reduced expression of stemness markers, including CD44 itself, after alpha-fetoprotein knockout, alongside inhibition of PI3K/Akt signaling. Another liver cancer study identified CD44 as a receptor for endotrophin and showed that CD44 engagement activated STAT3 signaling, promoting epithelial-mesenchymal transition, proliferation, and sorafenib resistance.

Several studies focused on CD44-directed delivery systems designed to improve therapeutic selectivity. Hyaluronic acid-based nanoparticles were used to enable CD44-mediated targeting in ovarian cancer, where co-delivery of paclitaxel and piperine enhanced cellular uptake, tumor accumulation, cytotoxicity, and apoptosis while reducing systemic toxicity. Similarly, biodegradable polymersomes functionalized with hyaluronic acid were engineered to target CD44-overexpressing triple-negative breast cancer cells and deliver gemcitabine with copper peroxide nanoparticles, producing reactive oxygen species, inducing immunogenic cell death, and improving anti-PD-L1 immunotherapy efficacy. A separate study developed CD44-targeted chitosan nanoparticles carrying ginsenoside Rg1 for diabetic kidney disease, aiming to restore mitochondrial homeostasis through AMPK/mTOR-mediated regulation of autophagy and pyroptosis.

CD44 was also implicated in immune regulation and stromal communication. In gastric cancer, tumor cell-derived serglycin was reported to signal through CD44 on T cells, especially Tregs, driving differentiation of LAG3-positive regulatory T cells and maintaining their suppressive function via a CD44-TGFβRI-SMAD3 pathway. Blocking SRGN-CD44 signaling reduced immunosuppression and inhibited tumor progression. In cirrhosis, CD44 was part of a protective CCL5-mediated hepatocyte-CD44+ plasmacytoid dendritic cell crosstalk associated with restored antibacterial immunity. In hepatocellular carcinoma, CD44 was further identified as a mediator of endotrophin-driven tumor-stroma cross-talk, linking fibrosis, inflammation, and malignant progression.

Beyond disease-specific mechanistic studies, CD44 also appeared in broader analyses of intercellular communication. A lifespan-dependent mouse tissue study found that CD44, together with ITGB1, showed highly dynamic changes across organs and timepoints, suggesting a role as a central node in predicted age-dependent communication shifts. Across these publications, CD44 was repeatedly positioned as a functional receptor or targeting marker in cancer, fibrosis-associated disease, immune modulation, and nanoparticle-based drug delivery.

Key Publications

  • NEWJul Adapalene inhibits the activity of CD44, a cancer stem cell biomarker in Triple negative breast cancer. (Molecular biology reports, 2026, PMID 42397497): "The primary cell surface receptor for ECM components is CD44."
  • NEWJul Anserine restores antibacterial immunity in cirrhosis via a protective CCL5-mediated hepatocyte-CD44+pDC crosstalk. (Journal of hepatology, 2026, PMID 42385859): "Anserine restores antibacterial immunity in cirrhosis via a protective CCL5-mediated hepatocyte-CD44+pDC crosstalk."
  • May Preliminary study on targeted nanoparticles co-loaded with piperine and paclitaxel prodrug for ovarian cancer treatment. (Journal of materials chemistry. B, 2026, PMID 42011733): "...to enable CD44-mediated tumor targeting."
  • Apr Quantitative profiling of lifespan-dependent cell-cell communication potential reveals dynamic ligand-receptor network shifts across mouse tissues. (PloS one, 2026, PMID 41860844): "For instance, CD44 and ITGB1 were found to undergo highly dynamic changes across timepoints and organs, suggesting that they may act as central nodes in predicted age-dependent communication changes."
  • May Biodegradable polymersomes encapsulating copper peroxide and gemcitabine for targeted chemoimmunotherapy. (Journal of controlled release : official journal of the Controlled Release Society, 2026, PMID 41780685): "...functionalized with hyaluronic acid (HA) to target CD44-overexpressing TNBC cells."
  • May Serglycin Drives LAG3+ Treg Differentiation and Immunosuppression in Gastric Cancer. (Cancer research, 2026, PMID 41734377): "Serglycin (SRGN), derived from tumor cells, facilitates tumor progression in gastric cancer primarily via its receptor CD44, which is highly expressed in T cells, especially Tregs."
  • May CD44-targeted chitosan nanoparticles delivering ginsenoside Rg1 restore mitochondrial homeostasis in diabetic kidney disease via AMPK/mTOR-mediated regulation of autophagy and pyroptosis. (Free radical biology & medicine, 2026, PMID 41707746): "This study aimed to construct CD44-targeted chitosan (Cs) nanoparticles encapsulating ginsenoside Rg1 (CD44-Cs@Rg1) for targeted delivery,"
  • May Endotrophin- and CD44-Mediated Heterotypic Signaling Mediates Tumor-Stroma Cross-talk and Facilitates Malignant Progression in Hepatocellular Carcinoma. (Cancer research, 2026, PMID 41671381): "Using peroxidase-catalyzed proximity labeling, we identified CD44 as an ETP receptor."
  • Apr Alpha-fetoprotein acts as a key regulator of cancer stemness in hepatocellular carcinoma via PI3K/Akt pathway. (Cellular signalling, 2026, PMID 41651174): "Comparative analyses demonstrated that AFP ablation markedly reduced tumorigenic potential in vivo, accompanied by downregulation of stemness markers (EPCAM and CD44) and inhibition of PI3K/Akt signaling."
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