Semaglutide Enhances Cellular Regeneration in Skin and Retinal Cells In Vitro

<b>Background/Objectives:</b> Glucagon-like peptide-1 (GLP-1) is an endogenous hormone with receptors widely expressed across multiple organs. GLP-1 receptor agonists (GLP-1RAs), primarily used for diabetes management, have demonstrated anti-inflammatory and antioxidant properties beyond glucose regulation. This study explores the protective effect of semaglutide, a GLP-1RA, in reducing oxidative stress and promoting wound healing in human dermal fibroblasts. Additionally, it assesses whether semaglutide offers the direct protection of retinal endothelial cells under oxidative stress. <b>Methods:</b> Human dermal fibroblasts and retinal endothelial cells were treated with semaglutide at concentrations ranging from 0 to 45 pg/mL for 24 h under oxidative stress induced by hydrogen peroxide (H₂O₂). Cell viability and ATP levels were measured via MTT and ATP assays. Apoptosis was evaluated using propidium iodide staining. Intracellular reactive oxygen species (ROS) and mitochondrial superoxide were assessed through confocal microscopy with specific fluorescent probes. Wound healing was tested using scratch assays, with closure monitored over time and quantified with ImageJ (version 1.51). Gene expression levels of antioxidants, extracellular matrix components, inflammatory cytokines, and MMPs (MMP3, MMP9) were determined via real-time PCR. <b>Results:</b> Semaglutide significantly improved cell viability and ATP production under oxidative stress (<i>p</i> < 0.001), while reducing apoptosis and intracellular ROS levels. It notably accelerated fibroblast wound closure, achieving near-complete restoration. Gene analysis revealed increased expression of antioxidant and ECM-related genes, along with decreased pro-inflammatory cytokines and MMPs, indicating reduced inflammation and enhanced tissue remodeling. <b>Conclusions:</b> Semaglutide offers robust antioxidative and cytoprotective effects in dermal fibroblasts and retinal endothelial cells, promoting wound healing. These findings highlight its therapeutic potential for diabetic foot ulcers and diabetic retinopathy, supporting further in vivo investigation.