Targeting CFTR Ubiquitination: Current Advances in Therapeutic Strategies for Cystic Fibrosis

Cystic fibrosis (CF) is a monogenic disease caused by mutations in the CF transmembrane conductance regulator (CFTR), whose folding, trafficking, and stability are tightly controlled by ubiquitination-dependent protein quality control (PQC) pathways. Although CFTR modulators have transformed CF therapy, their efficacy remains limited by persistent ubiquitination and degradation of rescued CFTR. This limitation is particularly evident in class I mutations, where premature termination codons (PTCs) reduce full-length CFTR protein production and no approved mutation-specific therapies are broadly available for canonical PTC variants. Recent advances highlight ubiquitination as a critical and druggable determinant of CFTR stability. The E3 ligase RFFL regulates peripheral CFTR PQC, restricting the stability of rescued CFTR at the plasma membrane (PM). Inhibition of RFFL, including via antisense oligonucleotides (ASO) and small molecules, enhances CFTR rescue and improves outcomes in combination with modulators and translational readthrough therapies. In parallel, deubiquitinase (DUB)-targeting chimeras (DUBTACs) have emerged as a novel modality to stabilize proteins by reversing ubiquitination. Here, we review current advances in targeting CFTR ubiquitination, with a focus on RFFL inhibition and DUBTAC-based strategies, and discuss their opportunities and translational limitations as components of next-generation CF therapies.