Licochalcone A Attenuates Oxidative Stress and Inflammation to Promote Second-Degree Burn Healing Through Nrf2/HO-1 Activation in Mice

Burn injury represents one of the most prevalent accidental traumas worldwide, contributing to substantial morbidity and mortality. Second-degree burns are frequently complicated by bacterial infection, excessive inflammation, and oxidative stress, which collectively impede wound healing. Licochalcone A (LCA), a bioactive flavonoid isolated from licorice, exhibits anti-inflammatory and antioxidant properties, yet its therapeutic role in burn wounds remains unexplored. Here, we evaluated the effects of a topical LCA-containing hydrogel on wound healing in a mouse dorsal second-degree scald model (100 °C, 5 s) and explored the associated molecular changes. In vivo, LCA-hydrogel treatment was associated with increased collagen deposition, reduced expression of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), reduced neutrophil and macrophage infiltration, and upregulated Ki67 and vascular endothelial growth factor C (VEGF-C). In hydrogen peroxide (H2O2)-stimulated fibroblasts, LCA attenuated reactive oxygen species (ROS) accumulation, improved cell viability and migration, preserved mitochondrial integrity, and restored antioxidant enzyme activities. Integrated transcriptomic and proteomic analyses identified 227 co-differentially expressed genes/proteins enriched in the reactive oxygen species pathway. Western blotting showed that the effects of LCA were associated with increased nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression and decreased Kelch-like ECH-associated protein (Keap1) expression. These exploratory findings suggest that the LCA-containing hydrogel is associated with accelerated second-degree burn healing, and that the antioxidant effects of LCA are associated with modulation of Keap1/Nrf2/HO-1 signaling, supporting further evaluation of its potential as a burn therapeutic candidate.