Semaglutide and Liraglutide Modulate Oxidative Stress and Wound Repair in Normal Human Skin Cells Exposed to an In Vitro Diabetic-like Environment

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) not only improve glycemic control but also possess anti-inflammatory and antioxidant properties. In this study, the effects of semaglutide and liraglutide on oxidative stress and wound healing were examined in human dermal fibroblasts (NHDFs) and keratinocytes (NHEKs) under diabetes-mimicking conditions. Cells were exposed to high glucose and hydrogen peroxide, followed by treatment with semaglutide or liraglutide at concentrations of 22.5 and 45 pg/mL for 48 h. We assessed cell viability, apoptosis, intracellular reactive oxygen species (ROS), Ki-67, and Pax-7. Advanced glycation end-products (AGEs) and their receptor (RAGE) were quantified via ELISA. Wound healing was evaluated by scratch assay, and the gene expression of antioxidants, cytokines, and matrix components was measured by real-time PCR. Semaglutide significantly improved NHDF viability and proliferation under diabetic conditions, reducing ROS production more effectively than liraglutide. Apoptosis decreased, evidenced by increased Bcl-2 alongside decreased Bax and cleaved caspase-3, particularly with semaglutide. Furthermore, semaglutide uniquely activated Pax-7 expression. While both agents upregulated antioxidants, semaglutide more effectively suppressed AGEs/RAGE and inflammatory cytokines. Both drugs enhanced collagen expression and accelerated wound closure; however, semaglutide achieved near-complete healing within 48 h. Neither drug induced observable changes in NHEKs. Semaglutide exhibits strong antioxidative, cytoprotective, and pro-regenerative effects in diabetic NHDFs, outperforming liraglutide across multiple parameters. These findings highlight semaglutide’s therapeutic potential for diabetic wound healing, warranting further in vivo investigation.