Ferulic Acid Modulates High Glucose-Induced MMP-1/TIMP-1 Imbalance and Enhances Wound Closure of Human Gingival Fibroblasts

Background/Objectives: Chronic hyperglycemia drives gingival fibroblast dysfunction, disrupting extracellular matrix homeostasis and the migratory capacity required for wound healing, which contributes to increased periodontal susceptibility in diabetes. Ferulic acid (FA), a dietary phenolic compound with antioxidant and anti-inflammatory properties, has demonstrated wound-healing activity in various tissues; however, its effects on human gingival fibroblasts (HGFs) under hyperglycemic conditions remain unclear. This study investigated the effects of FA on HGF viability, wound closure, and the secreted concentrations of matrix metalloproteinase-1 (MMP-1), tissue inhibitor of metalloproteinase-1 (TIMP-1), and interleukin-6 (IL-6) under normoglycemic and hyperglycemic conditions. Methods: Cultured HGFs (HGF-1 cell line) were pre-conditioned for 72 h under normal glucose (5.5 mM) or high glucose (25 mM), with an iso-osmolar mannitol control to distinguish glucose-specific effects from osmotic changes. Viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and wound closure by scratch assay following FA treatment, while MMP-1, TIMP-1, and IL-6 concentrations in conditioned medium were quantified by enzyme-linked immunosorbent assay (ELISA). Results: FA was non-cytotoxic at all tested concentrations, whereas 50 µM transiently increased viability. FA significantly enhanced wound closure under both conditions, independent of osmotic effects. High glucose increased IL-6 concentration in the conditioned medium (significant at 48 h) and MMP-1 levels. FA partially attenuated MMP-1 levels at specific time points, modestly reduced IL-6 levels, and markedly increased TIMP-1 concentration under both glucose conditions. Conclusions: FA enhanced wound closure in scratch assay and shifted the secreted MMP-1/TIMP-1 concentration ratio toward a more favorable, matrix-protective profile at the protein level, without cytotoxicity, supporting further investigation of its potential role in periodontal tissue repair under high glucose conditions.