卵巢肿瘤家族的去泛素化酶4(OTUD4)是OTU去泛素化酶家族的一员，已被认为在癌症中减少，以调控细胞凋亡。然而，OTUD4在烟草烟雾诱导的上皮细胞凋亡中的作用及其机制尚未阐明。在本研究中，我们表明OTUD4蛋白在经CSE处理的小鼠和气道上皮细胞中减少。OTUD4的沉默加重了经烟草烟雾提取物(CSE)处理的小鼠肺组织中的细胞凋亡和肺气肿变化。此外，在小鼠肺部恢复OTUD4有助于减轻CSE诱导的细胞凋亡和肺气肿形态学改变。OTUD4对细胞凋亡的作用也在体外得到了确认。通过蛋白质谱筛查，我们发现OTUD4可能与纤溶酶原激活物抑制剂1(PAI-1)相互作用。我们进一步证实OTUD4与PAI-1相互作用，以去泛素化并抑制CSE诱导的PAI-1降解。此外，OTUD4在气道上皮细胞凋亡中的保护作用被PAI-1失活所阻断。综上所述，我们的数据表明OTUD4通过调控PAI-1降解来调节烟草烟雾引起的气道上皮细胞凋亡。靶向OUTD4/PAI-1信号可能提供一个治疗肺部细胞凋亡者，用于对抗烟草烟雾诱导的肺气肿的治疗靶点。©2023. 作者。

Ovarian tumor family deubiquitinase 4 (OTUD4), a member of the OTU deubiquitinating enzyme, is implicated to decrease in cancer to regulate cell apoptosis. However, the role of OTUD4 in cigarette smoke induced epithelial cell apoptosis and its mechanism have not been elucidated. In this study, we showed that OTUD4 protein reduced in CSE treated mice and airway epithelial cells. OTUD4 silence aggravated cell apoptosis and emphysematous change in the lung tissue of cigarette smoke extract (CSE) treated mice. Additionally, restoration of OTUD4 in the lung of mice alleviated CSE induced apoptosis and emphysematous morphology change. The effect of OTUD4 on cell apoptosis was also confirmed in vitro. Through protein profile screening, we identified that OTUD4 may interact with plasminogen activator inhibitor 1(PAI-1). We further confirmed that OTUD4 interacted with PAI-1 for de-ubiquitination and inhibiting CSE induced PAI-1 degradation. Furthermore, the protective role of OTUD4 in airway epithelial cells apoptosis was blocked by PAI-1 deactivation. Taken together, our data suggest that OTUD4 regulates cigarette smoke (CS)-triggered airway epithelial cell apoptosis via modulating PAI-1 degradation. Targeting OUTD4/PAI-1 signaling might potentially provide a therapeutic target against the lung cell apoptosis in cigarette smoke (CS)-induced emphysema.© 2023. The Author(s).