Ferulic acid promotes wound healing through ACOD1-dependent redox balance and tissue regeneration.

BACKGROUND: Acute infected wounds remain a major clinical challenge owing to persistent inflammation, oxidative stress, and impaired angiogenesis. While natural phenolic compounds, like ferulic acid (FA), have antioxidant properties, their role in coordinating wound repair across immune and vascular cells remains unclear. PURPOSE: This study aims to elucidate the multi-modal mechanisms by which ferulic acid coordinates wound repair, focusing on its effects on redox regulation, immune modulation, and angiogenic activation in both cellular and murine models. METHODS: A combined in vitro and in vivo experimental approach was employed, using RAW264.7 macrophage and human umbilical vein endothelial cells (HUVECs) cultures, along with a full-thickness excisional wound model in mice, to investigate the therapeutic effects and molecular mechanisms of FA. Transcriptomic profiling and the role of Aconitate Decarboxylase 1 (ACOD1) were investigated via gene knockdown. RESULTS: FA effectively protected macrophages from oxidative injury by activating the Nrf2-Keap1 pathway, enhancing SOD/GPx activity, and suppressing NOX1 expression. In HUVECs under stress, FA restored proliferation, migration, and tube formation while increasing VEGF, TGF-β, and collagen I. Topically, FA accelerated wound healing in mice, reduced bacterial load, increased collagen deposition, and promoted angiogenesis. Transcriptomic analysis showed that FA reprograms the wound microenvironment by downregulating pro-inflammatory pathways (IL-17/TNF) and upregulating genes involved in extracellular matrix (ECM) and angiogenesis. ACOD1 was a required metabolic enzyme mediating FA's effects; its knockdown blocked FA's antioxidant, mitochondrial, and angiogenic effects. CONCLUSION: These findings elucidate a novel ACOD1-dependent pathway in which FA coordinates the resolution of oxidative stress and promotes tissue regeneration. FA emerges as a promising bioactive component for advanced wound-healing biomaterials.