The key role of hyaluronic acid molecular weight in HIF-1α pathway-mediated hypoxic microenvironment reprogramming

Hypoxia is a key factor in delaying chronic wound healing, so therapeutic strategies to alleviate tissue hypoxia are urgently needed. While oxygen-delivering materials have been studied, their long-term biosafety and stability remain unclear. Hyaluronic acid (HA) has shown tissue repair properties, but its role in alleviating hypoxic injury remains unknown. In this study, HA samples with different molecular weights (HA I, HA II, and HA III) were prepared through enzymatic hydrolysis. Structural characterization revealed that HA I exhibited a spherical conformation, while HA II and HA III possessed a flexible chain and semi-flexible chain conformations, respectively. Moreover, HA alleviated oxidative and inflammatory damage in hypoxic environments, with HA II (Mw ≈ 30.8 kDa) showing superior activity. Mechanistically, HIF-1α regulation is central to the anti-hypoxia activity of HA. The in vivo experiments demonstrated that HA II could promote angiogenesis and epidermal regeneration of hypoxic tissues. This study systematically revealed the structure-activity relationship between the molecular weight, chain conformation, and anti-hypoxia activity of HA, suggesting enzymatic hydrolysis as a promising strategy to enhance therapeutic potential of HA for hypoxic diseases.