Distinctive lipid signatures of bronchial epithelial cells associated with cystic fibrosis drugs, including Trikafta

Over the last years, a number of drugs have been approved for the treatment of cystic fibrosis (CF). Among them, the new Trikafta, a combination of three drugs, holds great promises to radically improve the quality of life for a large part of CF patients carrying one copy of the most frequent CFTR mutation: F508del. Currently available, disease-modifying, CF drugs work by rescuing the function of mutated CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) anion channel. Recent research work shows that membrane lipids, and the cell lipidome in general, play a significant role in the mechanism of CFTR defective trafficking and, on the other hand, in its rescue. In this paper, by using untargeted lipidomics on CFBE41o- cells, we identified distinctive changes in bronchial epithelial cell lipidome associated with treatment with the triple combination VX-661/VX-445/VX-770 (drug name: Trikafta) and other CF drugs. Particularly interesting is the reduction of ceramide levels, known molecular players in the induction of apoptosis, that appears to be associated with a decrease in cell susceptibility to undergo apoptosis. This evidence could account for additional beneficial role of the triple combination on CF phenotypes.