Sesamin Promotes Diabetic Wound Healing by Inhibiting Ferroptosis via the SIRT1 /Keap1/Nrf2 Pathway

ABSTRACT Diabetes mellitus frequently leads to diabetic wounds (DW), a serious complication for which current treatment options remain limited. This work examined the pro‐healing effects of sesamin (Sea), a major sesame lignan, on DW and the mechanisms underlying these effects. In vitro, human umbilical vein endothelial cells (HUVECs) were cultured under high glucose (HG) conditions to mimic diabetic dysfunction. Cell viability, lipid peroxidation, Fe 2+ accumulation, mitochondrial function, and expression of ferroptosis‐related proteins were assessed. Sirt1 knockdown was performed to verify target specificity. In vivo, a streptozotocin‐induced diabetic mouse model with full‐thickness skin wounds was established. Sea was administered, and wound healing rates, reactive oxygen species (ROS) levels, GPX4 expression, and transcriptomic profiles were analyzed. In vitro, Sea dose‐dependently ameliorated HG‐induced dysfunction in HUVECs and suppressed ferroptosis. Mechanistically, Sea upregulates Sirt1 expression, which promotes the dissociation of Keap1/Nrf2, thereby facilitating Nrf2 nuclear translocation and upregulating anti‐ferroptosis proteins expression. These effects were abrogated by Sirt1 knockdown. In vivo, transcriptomic analysis revealed ferroptosis inhibition as a key mechanism underlying Sea‐mediated DW healing. Sea treatment accelerated STZ‐induced DW closuring, reduced ROS levels, and upregulated GPX4 expression, effects that were diminished by Sirt1 silencing. Collectively, our findings demonstrate that Sea promotes DW healing by activating the Sirt1/Keap1/Nrf2 pathway to inhibit ferroptosis, positioning Sea as a promising therapeutic candidate for DW treatment.