Zhan Yuan, Deng Zhesong, Yang Ruonan, Chen Shanshan, Zhang Jiaheng, Zhang Yating, Fu Hao, Huang Qian, Gu Yiya, Zeng Zhilin, Chen Jinkun, Zhang Jixian, Wu Jixing, Xie Jungang
Department of Respiratory and Critical Care Medicine National Clinical Research Center of Respiratory Disease, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan Hubei China.
Department of Respiratory and Critical Care Medicine The First Affiliated Hospital of Chongqing Medical University Chongqing China.
MedComm (2020). 2025 Aug 29;6(9):e70345. doi: 10.1002/mco2.70345. eCollection 2025 Sep.
Chronic obstructive pulmonary disease (COPD) is a complex and irreversible respiratory disorder with a poor prognosis and a lack of effective pharmaceutical treatment. Our previous metabolomics study identified phytosphingosine (PHS) as a key differential metabolite in COPD that is positively correlated with lung function. In this study, we investigated the bioactive effects of PHS on experimental COPD and its underlying mechanisms using cigarette smoke (CS)-induced mouse and cell models. We found that administering PHS improved CS-induced lung dysfunction, emphysema, and airway inflammation by reducing cellular senescence and the senescence-associated secretory phenotype in bronchial epithelium. Mechanistically, PHS interacted with the free fatty acid receptor 4 (FFAR4) and upregulated its expression, leading to the modulation of STIP1 homology and U-Box containing protein 1 (STUB1) downstream, which controlled the ubiquitination levels of P53 and mitigated cellular senescence. Moreover, both FFAR4 overexpression through intratracheal injection of adeno-associated virus and the administration of the FFAR4 agonist TUG891 showed therapeutic effects on CS-induced lung damage. Our results highlight the beneficial impacts of PHS in experimental COPD mediated through the FFAR4 receptor, protecting against CS-induced bronchial epithelial cell senescence and suggesting PHS as a promising therapeutic agent for COPD.
慢性阻塞性肺疾病（COPD）是一种复杂且不可逆的呼吸系统疾病，预后较差且缺乏有效的药物治疗。我们之前的代谢组学研究确定植物鞘氨醇（PHS）是COPD中的关键差异代谢物，与肺功能呈正相关。在本研究中，我们使用香烟烟雾（CS）诱导的小鼠和细胞模型，研究了PHS对实验性COPD的生物活性作用及其潜在机制。我们发现，给予PHS可通过减少支气管上皮细胞的细胞衰老和衰老相关分泌表型，改善CS诱导的肺功能障碍、肺气肿和气道炎症。机制上，PHS与游离脂肪酸受体4（FFAR4）相互作用并上调其表达，导致下游含STIP1同源性和U-盒蛋白1（STUB1）的调节，从而控制P53的泛素化水平并减轻细胞衰老。此外，通过气管内注射腺相关病毒过表达FFAR4以及给予FFAR4激动剂TUG891均对CS诱导的肺损伤显示出治疗作用。我们的结果突出了PHS通过FFAR4受体介导对实验性COPD的有益影响，预防CS诱导的支气管上皮细胞衰老，并表明PHS是一种有前途的COPD治疗药物。
