USP7-mediated stabilization of Snail1 drives macrophage-to-myofibroblast transition and promotes postoperative peritoneal adhesions

Abstract Background Postoperative peritoneal adhesions (PPAs) are a common and serious complication following abdominal surgery. The key pathological basis is the excessive accumulation of myofibroblasts during adhesion formation. However, the cellular contributors to myofibroblasts accumulation and the regulatory mechanisms underlying this process remain poorly understood. Methods A mouse model of PPAs was established, and cellular experiments using immortalized bone marrow-derived macrophages (iBMDM) were conducted to investigate the role and mechanism of macrophage-to-myofibroblast transition (MMT). Transcriptome sequencing, RNA interference, dual luciferase reporter assays, co-immunoprecipitation (Co-IP), and ubiquitination assays were performed to investigate the molecular mechanisms, which were further validated by pharmacological intervention. Results The findings showed a substantial population of macrophages exhibiting myofibroblast-like characteristics in adhesion tissues. TGF-β1 significantly induced MMT by activating Smad3 signaling. Mechanistically, Smad3 transcriptionally upregulates Usp7 expression, which further stabilizes Snail1 protein through deubiquitination. Knockdown of Usp7 significantly inhibited MMT in iBMDMs and decreased Snail1 protein stability, without affecting its mRNA expression. In vivo experiments showed that inhibiting Smad3 or USP7 significantly reduced adhesion formation. Additionally, the screened small-molecule USP7-interacting compound Olaparib disrupts the interaction between USP7 and Snail1, promotes ubiquitin-mediated degradation of Snail1, and alleviates adhesion in a dose-responsive manner in vivo. Conclusion This study provides supportive evidence for the involvement of MMT in PPAs and identifies the TGF-β1/Smad3–USP7–Snail1 axis as a potential regulatory mechanism underlying this process. In addition, Olaparib was identified as a potential USP7-interacting compound capable of alleviating adhesions. The findings reveal that targeting USP7 may represent a promising strategy to prevent PPAs. Graphical Abstract Following peritoneal injury, TGF-β1 activates Smad3 signaling in macrophages, leading to transcriptional upregulation of Usp7 . USP7 stabilizes Snail1 through deubiquitination and promotes MMT-associated changes, thereby contributing to PPA formation. Pharmacological modulation of USP7/Snail1 axis by Olaparib enhances Snail1 degradation and attenuates adhesion development.