Mechanism of tectorigenin in promoting thermal burn wound healing via the Nrf2-mediated ferroptosis pathway: Integrated pharmacological and experimental study

Abstract

Thermal burn wounds cause extensive skin damage and delayed repair due to oxidative stress, inflammation, and ferroptosis. Tectorigenin (TG), a natural O-methylated isoflavone derived from Belamcanda chinensis, exhibits potent antioxidant and anti-inflammatory activities, yet its molecular mechanisms in burn wound repair remain unclear. This study systematically investigated the TG's therapeutic potential through network pharmacology, in vivo, and in vitro analyses. Network pharmacology predicted that TG targets were highly enriched in oxidative stress, inflammation, and angiogenesis-related pathways, with Nrf2 and its downstream effectors identified as core nodes. In a mouse partial-thickness burn model, topical TG (0.25-1 %) significantly accelerated wound contraction, enhanced collagen remodeling, and promoted neovascularization, as confirmed by H&E, Masson's trichrome staining, and CD34 immunohistochemistry. Western blotting and immunohistochemical analyses revealed dose-dependent upregulation of Nrf2, HO-1, GPX4, and SLC7A11, demonstrating activation of the Nrf2-HO-1/SLC7A11/GPX4 axis. ELISA results further showed reduced TNF-α and IL-6 levels, along with elevated VEGF expression, supporting the anti-inflammatory and pro-angiogenic effects. In H₂O₂-stimulated HaCaT cells, TG restored viability and migration, suppressed ROS production and lipid peroxidation, and enhanced Nrf2 pathway activation; notably, these protective effects were reversed by ML385, confirming Nrf2 dependence. Collectively, these findings demonstrate that TG promotes burn wound healing by activating Nrf2-mediated antioxidant and anti-ferroptotic defenses while regulating inflammation and angiogenesis, highlighting its promise as a natural therapeutic agent for oxidative stress-related skin injuries.

Keywords: Ferroptosis; GPX4; HO-1; Inflammation; Nrf2; Oxidative stress; SLC7A11; Tectorigenin; Thermal burn wounds.