A Sulfonamide-Based Compound DRZ-V Enhances Wound Repair via Macrophage-Mediated Responses Associated with TIRAP–NF-κB Signaling

Abstract

Background: Macrophage polarization is a critical determinant of wound healing outcomes, regulating the transition from inflammation to tissue repair. Failure to shift from a pro-inflammatory M1 phenotype to a reparative M2 phenotype contributes to chronic inflammation and delayed wound healing. Although the sulfonamide-based small molecule DRZ-V has shown anti-inflammatory properties, its role in macrophage functional reprogramming during wound repair has not been explored. This study investigated whether DRZ-V promotes macrophage phenotypic transition and enhances wound healing through modulation of TIRAP-mediated NF-κB signaling. Methods: Wound healing activity was evaluated using a full-thickness excisional wound model in mice. Macrophage polarization and cytokine expression were analyzed in RAW 264.7 macrophages by quantitative real-time PCR. The influence of macrophage-conditioned media on fibroblast migration was assessed using an in vitro scratch assay. TIRAP phosphorylation and NF-κB p65 activation were examined by immunoblotting and immunofluorescence analyses. Results: DRZ-V significantly accelerated wound closure in vivo. In macrophages, DRZ-V suppressed LPS-induced inflammatory responses by reducing pro-inflammatory cytokine expression while enhancing M2-associated markers, including Arg1, FIZZ1, and Ym1. DRZ-V also restored the expression of reparative mediators such as TGF-β and PDGF. Furthermore, conditioned media from DRZ-V-treated macrophages enhanced fibroblast migration, indicating indirect pro-reparative effects mediated through macrophage modulation. Mechanistically, these effects were associated with reduced TIRAP phosphorylation and attenuation of NF-κB activation. Conclusion: DRZ-V promotes wound repair by modulating macrophage-mediated inflammatory responses through inhibition of TIRAP–NF-κB signaling, highlighting its therapeutic potential for inflammatory and impaired wound healing conditions. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2026.