Targeting USP47 reprograms macrophage polarization to ameliorate septic peritonitis and promote cutaneous wound healing

Objective Dysregulation of M1/M2 macrophage polarization drives sepsis and impaired wound healing. Deubiquitinases (DUBs) are promisingdrug targets, but the role of ubiquitin-specific protease 47 (USP47) in macrophage plasticity remains unclear. This study investigated the regulatoryfunction of USP47 in macrophage polarization and its therapeutic potential for inflammatory disorders.Methods In vitro, human THP-1 and mouse bonemarrow-derived macrophages were polarized, with USP47 modulated via genetic manipulation or the inhibitor P22077. In vivo, LPS-induced septicperitonitis and cutaneous wound models were used to evaluate the effects of Usp47 deficiency or P22077 treatment. Mechanistically, protein interactionand ubiquitination assays were performed to verify the USP47-YAP axis and downstream signaling.Results USP47 was upregulated in M1 macrophagesand downregulated in M2 macrophages. USP47 inhibition skewed macrophages toward the M2 phenotype. In vivo , Usp47 knockout or P22077 treatmentimproved survival in septic mice, reduced systemic inflammation, and accelerated wound healing, accompanied by increased M2 infiltration at lesion sites.Mechanistically, USP47 directly deubiquitinated and stabilized YAP protein; stabilized YAP drove M1 polarization via two parallel axes: nucleartranslocation to promote pro-inflammatory cytokine transcription, and promotion of NLRP3 inflammasome stabilization.Conclusions USP47 is a critical regulator of macrophage polarization via the USP47-YAP-NLRP3 axis. Targeting USP47 exerts anti-inflammatory and pro-repair effects, representing a promising therapeutic strategy for sepsis and wound healing disorders.