Cystic fibrosis (CF) is a hereditary disease mostly related to ΔF508 CFTR mutation causing a proteinopathy that is characterized by multiple organ dysfunction, primarily lungs chronic inflammation, and infection. Defective autophagy and accumulation of the inflammatory lipid ceramide have been proposed as therapeutic targets. Accumulation of lipids and cholesterol was reported in the airways of CF patients, together with altered triglycerides and cholesterol levels in plasma, thus suggesting a disease-related dyslipidemia. Myriocin, an inhibitor of sphingolipids synthesis, significantly reduces inflammation and activates TFEB-induced response to stress, enhancing fatty acids oxidation and promoting autophagy. Myriocin ameliorates the response against microbial infection in CF models and patients' monocytes. Here we show that CF broncho-epithelial cells exhibit an altered distribution of intracellular lipids. We demonstrated that lipid accumulation is supported by an enhanced synthesis of fatty acids containing molecules and that Myriocin is able to reduce such accumulation. Moreover, Myriocin modulated the transcriptional profile of CF cells in order to restore autophagy, activate an anti-oxidative response, stimulate lipid metabolism and reduce lipid peroxidation. Moreover, lipid storage may be altered in CF cells, since we observed a reduced expression of lipid droplets related proteins named perilipin 3 and 5 and seipin. To note, Myriocin up-regulates the expression of genes that are involved in lipid droplets biosynthesis and maturation. We suggest that targeting sphingolipids de novo synthesis may counteract lipids accumulation by modulating CF altered transcriptional profile, thus restoring autophagy and lipid metabolism homeostasis.

囊性纤维化 (CF) 是一种遗传性疾病，主要与 ΔF508 CFTR 突变相关，导致蛋白质病，其特征是多器官功能障碍，主要是肺部慢性炎症和感染。已经提出有缺陷的自噬和炎症性脂质神经酰胺的积累作为治疗靶点。据报道，CF 患者的气道中存在脂质和胆固醇的积累，以及血浆中甘油三酯和胆固醇水平的改变，因此表明存在疾病相关的血脂异常。Myriocin 是一种鞘脂合成抑制剂，可显着减轻炎症并激活 TFEB 诱导的应激反应，增强脂肪酸氧化并促进自噬。Myriocin 可改善 CF 模型和患者单核细胞对微生物感染的反应。在这里，我们显示 CF 支气管上皮细胞表现出改变的细胞内脂质分布。我们证明了脂质积累得到了增强的含脂肪酸分子合成的支持，并且 Myriocin 能够减少这种积累。此外，Myriocin 调节 CF 细胞的转录谱以恢复自噬、激活抗氧化反应、刺激脂质代谢和减少脂质过氧化。此外，CF 细胞中的脂质储存可能会发生改变，因为我们观察到称为 perilipin 3 和 5 以及 seipin 的脂滴相关蛋白的表达降低。值得注意的是，Myriocin 上调了参与脂滴生物合成和成熟的基因的表达。