Mechanistic Evaluation of Luteolin in Wound Healing of Diabetic Foot Ulcer via Nrf2 Signaling

Abstract

Diabetic foot ulcers (DFUs) are a leading cause of lower‐limb amputation, with oxidative stress and ferroptosis playing critical roles in impaired wound healing. This study aimed to evaluate the therapeutic potential of luteolin (LU), a naturally occurring plant‐derived flavonoid, in DFU repair and to elucidate its underlying molecular mechanisms. A DFU rat model was established using a high‐fat/high‐glucose diet combined with streptozotocin injection, followed by full‐thickness skin wounding. LU was topically administered at different concentrations. Wound closure was monitored macroscopically, while histopathological changes, inflammatory cytokines, and growth factor levels were assessed by microscopy and ELISA. Network pharmacology and molecular docking analyses were performed to identify potential targets and signaling pathways, which were subsequently validated in vitro using human umbilical vein endothelial cells (HUVECs). LU significantly accelerated wound closure in a dose‐dependent manner, accompanied by reduced oxidative stress and pro‐inflammatory cytokine production, enhanced collagen deposition, increased angiogenesis, and upregulated expression of key growth factors. Bioinformatics analysis identified ferroptosis inhibition and activation of the nuclear factor erythroid 2–related factor 2 (Nrf2) signaling pathway as central mechanisms, which were confirmed experimentally. LU reduced intracellular reactive oxygen species levels and lipid peroxidation and promoted HUVEC migration and viability. Notably, pharmacological inhibition of Nrf2 with ML385 markedly reversed the protective effects of LU, indicating a pivotal role for Nrf2 signaling. Collectively, these findings demonstrate that LU promotes DFU healing through activation of Nrf2 signaling and suppression of ferroptosis, supporting its potential as a therapeutic candidate for the management of diabetic wounds.