Background <p>ADSCs and growth factor-based therapies are widely investigated for diabetic wound healing. However, the clinical translation of ADSCs is limited by their biological instability under hyperglycemic conditions, while exogenous growth factors face challenges such as short half-life and high production costs. Here, we propose a novel strategy using FGF21-engineered ADSCs (ADSC^FGF21), leveraging the dual advantages of stem cell paracrine effects and FGF21’s established role in metabolic regulation, to target ferroptosis and oxidative stress, key pathological drivers of delayed wound healing in diabetes.</p> Methods <p>To investigate ferroptosis in diabetic wounds, we quantified iron accumulation, DNA oxidative damage (8-OHdG), and lipid peroxidation (MDA assay) in diabetic wound tissues. In vitro, high glucose (HG) treated HUVEC, a model for endothelial dysfunction, were subjected to 7-AAD staining, BODIPY C11-based lipid peroxidation assays, and transmission electron microscopy (TEM) to assess ferroptosis hallmarks. The therapeutic effects of ADSC^FGF21 were evaluated through CCK-8 proliferation assays, scratch wound healing, and Matrigel-based tube formation assays under HG conditions. Mechanistic studies involved flow cytometry for ferroptosis distinction, qPCR/Western blot for SIRT1/NRF2/GPX4, AMPK pathway analysis, and immunofluorescence to track NF-κB p65 nuclear translocation.</p> Results <p>We demonstrated that hyperglycemia induces mitochondrial damage, lipid peroxidation, and ferroptosis in diabetic wounds and HG-treated HUVEC. By establishing FGF21-overexpressing ADSCs (ADSC^FGF21), we observed enhanced secretion of FGF21, which significantly attenuated HG-induced oxidative stress and restored endothelial cell viability. ADSC^FGF21 promoted angiogenesis and accelerated scratch closure. Mechanistically, ADSC^FGF21 upregulated NAD⁺ levels, activating the SIRT1/NRF2 axis, which subsequently enhanced GPX4 expression and suppressed lipid peroxidation. Importantly, AMPK phosphorylation was required for SIRT1/NRF2 axis activation and NF-κB p65 nuclear translocation was inhibited. In diabetic mice, ADSC^FGF21 transplantation accelerated wound closure and improved blood perfusion.</p> Conclusions <p>Our study establishes ADSC^FGF21 as a multimodal therapy for diabetic wounds, synergizing stem cell-mediated tissue repair with FGF21’s metabolic regulation. By activating the SIRT1/NRF2/GPX4 axis, ADSC^FGF21 restores redox homeostasis and blocks ferroptosis. These findings provide a promising strategy for chronic wound management.</p> Graphical abstract <p></p>