Cystic fibrosis (CF) is a genetic disorder caused by CFTR mutations, most commonly ΔF508, leading to defective ion transport and multisystem pathology. Small-molecule modulators partially restore mutant CFTR function, but therapeutic efficacy remains limited, particularly for N1303K mutation refractory to current treatments. Here, we show that inhibition of the glutaminyl-peptide cyclotransferase (QPCT)-dependent pathway rescues both the surface expression and functional activity of ΔF508 CFTR. Integrated molecular and physiological analyses identify protein disulfide-isomerase A4 (PDIA4) as a key mediator of this rescue via its pyroglutamate (pGlu)-dependent interaction with ΔF508 CFTR, which is essential for surface trafficking. Furthermore, inhibition of QPCT also restores the function of the N1303K CFTR mutant, revealing a broader mechanistic relevance of this pathway in correcting CFTR misfolding and trafficking defects. These findings uncover a generalizable mechanism for correcting CFTR folding abnormalities and suggest new therapeutic strategies for mutations unresponsive to existing modulators.