Medium-molecular weight hyaluronic acid orchestrates hair follicle regeneration via CD44/AKT-driven endogenous ROS activation of β-catenin

  • Int J Biol Macromol. 2026 May:360:151752. doi: 10.1016/j.ijbiomac.2026.151752.
Jing Liu  1 ,  Meishan Piao  2 ,  Yonghua Zhou  3 ,  Cheng Yang  4 ,  Bingtian Zhao  5
Affiliations
  • 1. Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering, Jiangnan University, Wuxi, 214122, China.
  • 2. Department of Dermatology, The Affiliated Wuxi No.2 People's Hospital, Wuxi, 214001, China.
  • 3. Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, 214064, China.
  • 4. Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering, Jiangnan University, Wuxi, 214122, China. Electronic address: [email protected].
  • 5. Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering, Jiangnan University, Wuxi, 214122, China. Electronic address: [email protected].
PMID: 41935804 DOI: 10.1016/j.ijbiomac.2026.151752
Abstract

Hair loss remains a challenging disorder with limited treatment options. While Reactive Oxygen Species (ROS) signaling plays a pivotal role in hair follicle regeneration, strategies to modulate endogenous ROS levels without external devices remain scarce. Given the emerging role of Polysaccharides in redox regulation, this study develops a series of molecular weight-defined hyaluronic acid (HA) fractions through controlled enzymatic cleavage to induce endogenous ROS production, leading to accelerated hair follicle regeneration. HA preserves the hair-inductive capacity of dermal papilla cells through elevated ALP activity, enhanced migratory behavior, accelerated G1/S transition, and upregulation of anagen-associated morphogens. Mechanistically, HA triggers endogenous mitochondrial ROS biosynthesis in a CD44-dependent manner, leading to Akt phosphorylation and β-catenin stabilization. Notably, our results reveal a defined molecular weight window for optimal activity, with HA III (268.1 kDa) being the most effective. HA application to hair loss mouse skin also significantly enhanced β-catenin expression and stimulated hair follicle development, with HA III showing particularly pronounced hair growth-promoting effects. Our findings uncover a molecular weight-activity relationship that precisely modulates beneficial endogenous ROS biosynthesis, establishing molecular weight-tailored HA as a multifunctional, device-independent biomaterial for hair loss and Other ROS-related regenerative disorders.

Keywords
CD44 signaling; Endogenous ROS; Hair follicle regeneration; Hyaluronic acid; Molecular weight–activity relationship.
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