CFTR modulators such as Kaftrio (elexacaftor/tezacaftor/ivacaftor) have markedly improved the rescue of F508del-CFTR in people with cystic fibrosis. Nevertheless, the rescued protein remains only partially stable and functional, highlighting the need for complementary strategies to further optimize therapeutic efficacy.
Previous studies (FFC#2/2018 and FFC#2/2020) identified two membrane lipids, ganglioside GM1 and cholesterol, whose exogenous supplementation enhances CFTR stability. In addition, GM1 exerts immunomodulatory effects by reducing the production of pro-inflammatory mediators. CFTR stability is also strongly influenced by infection with Pseudomonas aeruginosa (Pa).

This study investigated whether GM1 and cholesterol could potentiate the effects of Kaftrio on mutant CFTR rescue under conditions of Pa infection, and examined the role of GM1 in host–pathogen interactions using in vitro and in vivo cystic fibrosis models.

Researchers found that the F508del mutation disrupts cellular lipid homeostasis, altering GM1 and cholesterol levels. While Kaftrio promotes CFTR maturation, it does not fully restore lipid balance on its own.
Supplementation with GM1 and cholesterol further increased the stability and functional activity of Kaftrio-rescued CFTR, including in selected rare mutations. Notably, GM1 promoted CFTR retention at the plasma membrane, thereby enhancing modulator efficacy.
Moreover, GM1 improved cellular clearance of Pseudomonas aeruginosa, independently of CFTR modulator activity. In animal models, GM1 administration facilitated bacterial clearance and reduced lung inflammation.

Collectively, these findings highlight the critical role of membrane lipid composition in regulating both CFTR stability and host immune responses. Combining lipids such as GM1 and cholesterol with CFTR modulators may therefore represent a promising strategy to enhance therapeutic benefit and strengthen defense against infection in people with cystic fibrosis.