Abstract
Hyaluronic acid (HA) is widely used in medical, cosmetic, and nutraceutical applications, yet the systemic fate of orally administered HA, particularly non-animal forms, remains poorly characterised. This study investigates the stability, absorption, metabolism, and biological effects of a novel fungal-derived HA extracted from Tremella fuciformis using a sequential in vitro multi-barrier model simulating human physiological compartments, including gastric, intestinal, hepatic, renal, chondrocyte, and keratinocyte environments. Across the gastrointestinal stages, fungal-derived HA demonstrated high structural stability, maintained molecular weight, and exerted superior antioxidant and anti-inflammatory activity compared with sodium hyaluronate. It efficiently crossed the intestinal barrier without increasing hyaluronidase activity, indicating protection from premature enzymatic degradation. In hepatic cells, fungal-derived HA exhibited reduced intracellular uptake and greater extracellular persistence, suggesting lower first-pass metabolism and suggesting improved persistence under in vitro conditions. At peripheral targets, it increased the cluster of differentiation 44 (CD44) expression and HA internalisation in chondrocytes and keratinocytes, supporting anti-inflammatory and pro-regenerative effects. Renal assessments revealed minimal excretion and no cytotoxicity, supporting potential systemic availability. Overall, these results provide the first integrated in vitro evidence describing the absorption, distribution, metabolism, and excretion process of fungal-derived HA. This supports the conclusion that this form of HA is stable, biocompatible, and bioactive with therapeutic potential for joint and skin health, as suggested by the in vitro models.