Beyond CFTR: Ivacaftor's role in restoring cellular redox balance and preventing ferroptosis.

Cystic fibrosis (CF), is a genetic disorder caused by dysfunctional Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, characterized by progressive pulmonary decline and elevated oxidative stress and inflammation. CFTR modulators, including potentiators such as ivacaftor, represent the cornerstone of current therapeutic strategies. We present compelling evidence that ivacaftor, in contrast to other CFTR modulators, exhibits a CFTR-independent ability to mitigate oxidative injury by inhibiting lipid peroxidation, a cascade of oxidative damage, and by blocking ferroptosis, a specific form of cell death driven by unrestrained lipid oxidation. This protective mechanism is attributed to ivacaftor's direct action as a scavenger of lipid radicals, effectively interrupting the initiation and propagation of lipid peroxidation as well as decreasing its toxic products. Moreover, we demonstrate that ivacaftor acts as a regulator of cellular innate antioxidant defense pathways, restoring physiological levels of Nrf2 and GPx4, and upregulating the expression of FSP1. These findings reveal a previously unexplored aspect of ivacaftor's pharmacological profile, suggesting potential therapeutic applications extending beyond the realm of CF, particularly in disease contexts characterized by elevated oxidative stress and ferroptotic cell death.