Cystic fibrosis (CF) is caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel in epithelial organs leading to a complex multi-organ disease. CFTR modulator drugs improve mutant CFTR function and markedly improve clinical outcomes in people with CF (pwCF), but their broader molecular and systemic effects remain to be fully elucidated. We employed mass-spectrometry-based proteomics to compare the plasma and serum proteomes of pwCF treated with the dual combination CFTR modulator lumacaftor/ivacaftor (LUM/IVA) or the triple combination of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA). We found specific and common signatures associated with inflammation and metabolic processes. ELX/TEZ/IVA showed more consistent effects that were directed toward profiles in healthy individuals. Our findings indicate that ELX/TEZ/IVA leads to broader improvements in protein dysregulation than LUM/IVA in pwCF. Residual proteome changes may inform future therapeutic strategies for CF. A record of this paper's transparent peer review process is included in the supplemental information.
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