气道上皮细胞中FOXA1介导的CEPT1缺失通过内质网应激-线粒体功能障碍轴驱动哮喘发生发展
2026/07/31
摘要：
哮喘常伴随甘油磷脂代谢紊乱与磷脂酰胆碱（PC）水平下降，但其分子机制尚未完全阐明。本研究通过整合数据分析发现，甘油磷脂合成关键酶CEPT1在哮喘患者气道上皮中表达显著下调。CEPT1 表达不足会造成磷脂酰胆碱/磷脂酰乙醇胺（PC/PE）比值降低、磷脂稳态失衡，全面激活三条内质网（ER）应激通路，扰乱内质网钙库稳态，并引发线粒体钙超载，最终诱导线粒体氧化应激。研究证实，补充多烯磷脂酰胆碱（PPC）可恢复内质网与线粒体功能稳态，减少细胞凋亡、炎症因子释放以及黏液过量分泌。同时本研究确定FOXA1是 CEPT1 的直接转录激活因子。动物体内实验表明，CEPT1过表达能够减轻气道炎症与黏液高分泌。综上，本研究阐明了一条信号调控轴：FOXA1 表达受抑会导致 CEPT1 下调，进而破坏钙稳态、诱发内质网与线粒体功能障碍，最终造成黏液分泌和气道炎症。该研究提示，恢复 CEPT1 表达或补充 PPC，有望成为哮喘新型干预手段。
FOXA1-mediated CEPT1 deficiency in airway epithelium drives asthma via an ER stress-mitochondrial dysfunction axis
Qile Chen ,Yuyi Huang ,Junjie Wen ,Canyang Liang ,Yuhuan Wen ,Jing Wang ,Suda Gu ,Honglv Chen ,Sijie Wu ,Enli Zhang ,Bowen Sun ,Qingling Zhang ,Jie Yan
Cell Rep. 2026 May 22;45(6):117368. doi: 10.1016/j.celrep.2026.117368.
Abstract:
Asthma is associated with disordered glycerophospholipid metabolism and decreased phosphatidylcholine (PC), but the molecular basis remains incompletely defined. Through integrative data mining, we identify CEPT1, a key enzyme in glycerophospholipid biosynthesis, to be significantly downregulated in the airway epithelium of asthma. CEPT1 deficiency causes PC/PE reduction and phospholipid imbalance, activates all three endoplasmic reticulum (ER) stress pathways, disturbs ER Ca2+ stores, and drives mitochondrial Ca2+ overload, which in turn triggers mitochondrial oxidative stress. Notably, administration of polyenylphosphatidylcholine (PPC) restores ER and mitochondrial homeostasis and reduces apoptosis, cytokine release, and mucus overproduction. FOXA1 is identified as a direct transcriptional activator of CEPT1. In vivo, CEPT1 overexpression alleviates airway inflammation and mucus hypersecretion. Collectively, our study elucidates an axis wherein FOXA1-mediated CEPT1 repression induces ER stress and mitochondrial dysfunction through disrupted calcium handling, driving mucin hypersecretion and airway inflammation-identifying CEPT1 restoration or PPC as potential mechanism-based interventions for asthma.
哮喘常伴随甘油磷脂代谢紊乱与磷脂酰胆碱（PC）水平下降，但其分子机制尚未完全阐明。本研究通过整合数据分析发现，甘油磷脂合成关键酶CEPT1在哮喘患者气道上皮中表达显著下调。CEPT1 表达不足会造成磷脂酰胆碱/磷脂酰乙醇胺（PC/PE）比值降低、磷脂稳态失衡，全面激活三条内质网（ER）应激通路，扰乱内质网钙库稳态，并引发线粒体钙超载，最终诱导线粒体氧化应激。研究证实，补充多烯磷脂酰胆碱（PPC）可恢复内质网与线粒体功能稳态，减少细胞凋亡、炎症因子释放以及黏液过量分泌。同时本研究确定FOXA1是 CEPT1 的直接转录激活因子。动物体内实验表明，CEPT1过表达能够减轻气道炎症与黏液高分泌。综上，本研究阐明了一条信号调控轴：FOXA1 表达受抑会导致 CEPT1 下调，进而破坏钙稳态、诱发内质网与线粒体功能障碍，最终造成黏液分泌和气道炎症。该研究提示，恢复 CEPT1 表达或补充 PPC，有望成为哮喘新型干预手段。
（四川大学华西医院呼吸与危重症医学科 邓稞 王霁 王刚 译）
FOXA1-mediated CEPT1 deficiency in airway epithelium drives asthma via an ER stress-mitochondrial dysfunction axis
Qile Chen ,Yuyi Huang ,Junjie Wen ,Canyang Liang ,Yuhuan Wen ,Jing Wang ,Suda Gu ,Honglv Chen ,Sijie Wu ,Enli Zhang ,Bowen Sun ,Qingling Zhang ,Jie Yan
Cell Rep. 2026 May 22;45(6):117368. doi: 10.1016/j.celrep.2026.117368.
Abstract:
Asthma is associated with disordered glycerophospholipid metabolism and decreased phosphatidylcholine (PC), but the molecular basis remains incompletely defined. Through integrative data mining, we identify CEPT1, a key enzyme in glycerophospholipid biosynthesis, to be significantly downregulated in the airway epithelium of asthma. CEPT1 deficiency causes PC/PE reduction and phospholipid imbalance, activates all three endoplasmic reticulum (ER) stress pathways, disturbs ER Ca2+ stores, and drives mitochondrial Ca2+ overload, which in turn triggers mitochondrial oxidative stress. Notably, administration of polyenylphosphatidylcholine (PPC) restores ER and mitochondrial homeostasis and reduces apoptosis, cytokine release, and mucus overproduction. FOXA1 is identified as a direct transcriptional activator of CEPT1. In vivo, CEPT1 overexpression alleviates airway inflammation and mucus hypersecretion. Collectively, our study elucidates an axis wherein FOXA1-mediated CEPT1 repression induces ER stress and mitochondrial dysfunction through disrupted calcium handling, driving mucin hypersecretion and airway inflammation-identifying CEPT1 restoration or PPC as potential mechanism-based interventions for asthma.
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