USP7 inhibition promotes wound healing by suppressing M1 macrophage polarization via NF-κB/MAPK signaling pathway

Chronic wounds represent a significant clinical challenge due to their impact on patient quality of life and healthcare costs, necessitating innovative therapeutic strategies. USP7 is an important member of the deubiquitinating enzyme family. Several studies have shown that USP7 promotes M1 polarization of macrophages and inhibits M2 polarization through various pathways in the tumour environment. However, it is unclear whether USP7 also promotes M1 polarization of macrophages in a wound inflammatory environment. This study aims to elucidate the role of Ubiquitin-specific peptidase 7 (USP7) in modulating M1 macrophage polarization and its underlying mechanisms in wound healing. Utilizing both in vitro and in vivo models, we investigated the effects of USP7 on M1 macrophage polarization and wound healing outcomes. Our findings indicate that USP7 inhibition significantly reduces M1 macrophage polarization, as evidenced by the levels of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α being significantly lower than the control group when Usp7 is knockout (P < 0.05). Furthermore, we observed that Usp7-cKO in BMDM suppresses the NF-κB and MAPK signaling pathways, indicating a shift towards an anti-inflammatory phenotype. Additionally, Usp7-cKO has nearly doubled the migration and proliferation of fibroblasts in the inflammatory environment compared to the control group. Importantly, mice with Usp7-cKO in BMDM markedly improved wound healing efficiency in murine models and promoted angiogenesis. In conclusion, our study provides novel insights into the regulatory mechanisms of USP7 in M1 macrophage polarization and its potential therapeutic applications for wound management, paving the way for future research aimed at developing small molecule inhibitors targeting USP7 to improve tissue repair outcomes.