Targeting CD44-Hyaluronic Acid Signalling in Obesity Treatment - Insights from Small Molecules and Nanobioconjugates

Sep 30, 2026

Uploaded by Mary Man

Obesity is a complex metabolic disorder linked to chronic low-grade inflammation, insulin resistance, and increased risk of comorbidities such as cardiovascular disease and type 2 diabetes mellitus. The transmembrane glycoprotein CD44 interacts with hyaluronic acid, a key extracellular matrix component, to control adipogenesis, immune cell infiltration, and metabolic dysfunction. Dysregulated CD44-HA signaling drives adipose hypertrophy, macrophage recruitment, and activation of proinflammatory pathways including NF-κB and MAPKs, worsening metabolic imbalance. This review analyzes CD44-HA roles in obesity and assesses therapies targeting the axis, comparing small-molecule inhibitors and nanobioconjugates and discussing future combinatorial and personalized approaches.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages29

Reading Time1 h 13 min

AccessFree to download

Abstract

Keywords

Introduction

Obesity as a metabolic disorder

Global public health impact

Targeting CD44-Hyaluronic Acid Signalling in Obesity Treatment: Insights from Small Molecules and Nanobioconjugates Nutrition and Metabolic Insights Volume 19: 1-29 © The Author(s) 2026 Article reuse guidelines: [sagepub.com/journals-permissions](sagepub.com/journals-permissions)[ ](sagepub.com/journals-permissions)[DOI: 10.1177/11786388251408961](DOI: 10.1177/11786388251408961)[ ](DOI: 10.1177/11786388251408961)[journals.sagepub.com/home/nmi](journals.sagepub.com/home/nmi) Daniel Ejim Uti 1,2, Wilson Achu Omang3, Esther Ugo Alum 1, Okechukwu Paul-Chima Ugwu 1, Margaret Amieibi Wokoma4, Rowland Inalegwu Oplekwu5, Item Justin Atangwho4 and Godwin Eneji Egbung4 Abstract Obesity is a complex metabolic disorder associated with chronic low-grade inflammation, insulin resistance, and heightened risk of comorbidities such as cardiovascular diseases and type 2 diabetes mellitus (T2DM) . The Cluster of Differentiation 44 (CD44), a transmembrane glycoprotein, interacts with hyaluronic acid (HA), a major extracellular matrix (ECM) component, to regulate adipogenesis, immune cell infiltration, and metabolic dysfunction. Dysregulation of the CD44-HA signalling axis promotes adipose tissue hypertrophy, macrophage infiltration, and activation of proinflammatory pathways, including nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs), which further aggravate metabolic disturbances. This review provides a comprehensive analysis of CD44-HA signalling in the pathophysiology of obesity and evaluates therapeutic strategies targeting this axis. Small-molecule inhibitors, such as CD44 antagonists and hyaluronan biosynthesis modulators (eg, 4-methylumbelliferone), offer advantages in synthesis, bioavailability, and cost-effectiveness, but face challenges related to limited specificity, systemic toxicity, and potential resistance. In contrast, Nanobioconjugates engineered nanoparticles conjugated with biomolecules such as HA enable targeted delivery to CD44-overexpressing adipose tissues, enhance therapeutic efficacy, prolong drug release, and minimize off-target effects. Examples include lipid-based nanoparticles, polymer-based nanocarriers, and HA-functionalized systems, all of which show promise in preclinical models of obesity. Comparative analysis underscores the superior specificity and bioavailability of nanobioconjugates, though issues of large-scale production, immunogenicity, and regulatory approval remain. Combining nanobioconjugates with small molecules may optimize treatment outcomes by leveraging synergistic mechanisms. Emerging strategies including high-affinity HA ligands, monoclonal antibodies, RNA-based therapeutics, and artificial intelligence (AI) guided drug design, offering new opportunities for precision obesity management. Future directions highlight the importance of personalized and combinatorial therapies, supported by biomarker profiling and gene editing technologies such as CRISPR, to overcome current limitations in CD44-HA-targeted interventions. Keywords CD44-hyaluronic acid signaling, obesity pathogenesis, adipogenesis and inflammation, insulin resistance, small-molecule inhibitors, nanobioconjugates Received: 13 March 2025; accepted: 3 December 2025 1 Department of Research and Publications, Kampala International University, Uganda 2Department of Biochemistry, Faculty of Basic Medical Sciences, College of Medicine, Federal University of Health Sciences, Otukpo, Benue State, Nigeria 3Department of Medical Laboratory Sciences, College of Health Technology, Calabar, Cross River State, Nigeria 4Department of Biochemistry, Faculty of Basic Medical Sciences, University of Calabar, Nigeria 5Department of Biochemistry, Faculty of Basic Medical Sciences, Federal University of Allied Health Sciences, Enugu, Nigeria Corresponding author: Daniel Ejim Uti, Department of Biochemistry, Research and Publications, Kampala International University, Kampala 20000, Uganda. Departme

FAQs

How does CD44-Hyaluronic Acid signaling contribute to obesity pathophysiology?

CD44 interacts with hyaluronic acid to regulate adipogenesis, immune cell infiltration, and metabolic dysfunction. When the CD44-HA axis is dysregulated, it promotes adipose tissue hypertrophy, macrophage infiltration, and proinflammatory signaling such as NF-κB and MAPKs.

What advantages do small-molecule inhibitors have, and what limitations are noted?

Small-molecule inhibitors (including CD44 antagonists and hyaluronan biosynthesis modulators like 4-methylumbelliferone) can offer benefits in synthesis, bioavailability, and cost-effectiveness. Limitations include limited specificity, systemic toxicity, and potential resistance.

Why are nanobioconjugates considered promising for targeted obesity therapy?

Nanobioconjugates use engineered nanoparticles conjugated with biomolecules such as hyaluronic acid to enable targeted delivery to CD44-overexpressing adipose tissues. They can enhance therapeutic efficacy, prolong drug release, and reduce off-target effects, though manufacturing scale, immunogenicity, and regulatory approval remain challenges.

Sep 30, 2026

Uploaded by Mary Man