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<p>Sepsis is a major cause of acute lung injury (ALI) characterized by inflammatory responses. Ubiquitination plays a critical role in the pathogenesis of ALI. This study aimed to investigate the role of USP50, a deubiquitinating enzyme, in sepsis-induced ALI and its underlying molecular mechanisms. THP-1 cells were differentiated into macrophages and exposed to lipopolysaccharide (LPS) to establish an in vitro injury model. Pyroptosis was assessed using immunoblotting, flow cytometry, and enzyme-linked immunosorbent assay. The regulation of USP50 on NLRP3 deubiquitination was analyzed through immunoprecipitation, immunoblotting, and protein stability assays. The in vivo function of USP50 was evaluated using a cecal ligation and puncture (CLP)-induced septic mouse model. Results demonstrated that USP50 expression was significantly upregulated in the blood of patients with sepsis-induced ARDS and in the lungs of CLP-treated mice. USP50 knockdown suppressed pyroptosis in LPS-stimulated macrophages and septic mice. Furthermore, USP50 inhibition enhanced NLRP3 degradation by facilitating K48-linked ubiquitination. Overexpression of NLRP3 reversed the anti-pyroptotic effects induced by USP50 depletion in macrophages. In conclusion, USP50 suppression attenuates macrophage pyroptosis through inhibition of NLRP3 deubiquitination, thereby reducing lung injury in sepsis-induced models. These findings identify USP50 as a potential therapeutic target for sepsis-associated acute lung injury.</p>

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Interfering with USP50 expression inhibits macrophage pyroptosis in sepsis-induced acute lung injury by degrading NLRP3 protein

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月23日

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  • Shanshan Hu,
  • Jingjing Hu,
  • Shengnan Shu,
  • Yuexuan Chen,
  • Lu Wang

摘要

Sepsis is a major cause of acute lung injury (ALI) characterized by inflammatory responses. Ubiquitination plays a critical role in the pathogenesis of ALI. This study aimed to investigate the role of USP50, a deubiquitinating enzyme, in sepsis-induced ALI and its underlying molecular mechanisms. THP-1 cells were differentiated into macrophages and exposed to lipopolysaccharide (LPS) to establish an in vitro injury model. Pyroptosis was assessed using immunoblotting, flow cytometry, and enzyme-linked immunosorbent assay. The regulation of USP50 on NLRP3 deubiquitination was analyzed through immunoprecipitation, immunoblotting, and protein stability assays. The in vivo function of USP50 was evaluated using a cecal ligation and puncture (CLP)-induced septic mouse model. Results demonstrated that USP50 expression was significantly upregulated in the blood of patients with sepsis-induced ARDS and in the lungs of CLP-treated mice. USP50 knockdown suppressed pyroptosis in LPS-stimulated macrophages and septic mice. Furthermore, USP50 inhibition enhanced NLRP3 degradation by facilitating K48-linked ubiquitination. Overexpression of NLRP3 reversed the anti-pyroptotic effects induced by USP50 depletion in macrophages. In conclusion, USP50 suppression attenuates macrophage pyroptosis through inhibition of NLRP3 deubiquitination, thereby reducing lung injury in sepsis-induced models. These findings identify USP50 as a potential therapeutic target for sepsis-associated acute lung injury.