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Background <p>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.</p> Methods <p>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 <i>in vitro</i> scratch assay. TIRAP phosphorylation and NF-κB p65 activation were examined by immunoblotting and immunofluorescence analyses.</p> Results <p>DRZ-V significantly accelerated wound closure <i>in vivo</i>. 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.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年6月17日

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  • Sk Rameej Raja,
  • Alexander G. Obukhov,
  • Gajanan N. Darwhekar,
  • Chinmay Y. Majmudar,
  • Krishnaprasad Nair,
  • Shubham Kumar Behera,
  • Shreya Bharti,
  • Rigzin Yangdol,
  • Anil Prajapati,
  • Mirza S. Baig

摘要

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.