Fisetin-Mediated Topical Modulation of Senescent Cells in Skin Improves Wound Healing Dynamics in Diabetic Mice

OBJECTIVE: Diabetes mellitus affects over 25% of adults aged 65+ in the United States and is associated with a heightened risk of developing diabetic foot ulcers. Accumulation of senescent cells within the wound microenvironment can impair cutaneous repair, and senolytic therapies offer a promising approach to accelerate wound healing. APPROACH: In this study, topical fisetin, a flavonoid that promotes apoptosis of senescent cells, was evaluated for its impact on diabetic wound repair. Full-thickness excisional wounds were created on the dorsal skin of diabetic (db/db) mice. Animals were randomized to receive either topical vehicle (n = 12) or fisetin (n = 12) for three consecutive days per week, and wound healing outcomes were longitudinally assessed. RESULTS: Topical fisetin significantly increased the ratio of healthy dermis to granulation by day 7 (p = 0.04) and reduced dermal fibrosis by day 21 (p = 0.03). Fisetin decreased p16+ cells (p = 0.01) but increased p21+ cells (p = 0.02) at day 7 in the dermis, indicating varied effects on senescent cells. M1 macrophages (CD80+) were decreased in the fisetin-treated group (p = 0.05) at day 21, accompanied by a decrease in pro-inflammatory senescence-associated secretory phenotype cytokines, tumor necrosis factor alpha (p = 0.03), and interleukin-1beta (p = 0.01) at day 7. INNOVATION: Fisetin is the first topical seno-modulatory agent shown to enhance wound repair when administered after injury onset. Its favorable safety and efficacy in both modulating senescence and inflammation highlight its potential as a novel therapy for diabetic wounds. CONCLUSION: Topical fisetin enhances diabetic wound healing by reducing fibrosis and promoting healthy dermal regeneration through senescence and inflammation modulation. [Figure: see text].