Cystic fibrosis is an autosomal recessive disease in which mutations in the CFTR gene lead to a reduced life expectancy in carriers, partly due to the rapid loss of respiratory functions. CFTR-F508del is the most frequent mutation, leading to a mislocalized and non-functional CFTR protein. The tri-therapy Elexacaftor/Tezacaftor/Ivacaftor is now given to patients carrying CFTR-F508del mutation, but some biological defaults of this mutation are still not addressed. Among CFTR interactors, we have previously identified COMMD1 as a potential therapeutic target, which overexpression favors the plasma membrane expression of CFTR. In 2013, a cell-penetrating peptide named CIGB-552 was discovered as a COMMD1 protein stabilizer. We evaluate the therapeutic potential of CIGB-552 in cystic fibrosis context. FITC Tagged version of CIGB-552 was used to evaluate its uptake on cell models cultured submerged or in air-liquid interface. HS-eYFP assay was performed for measuring CFTR quenching ratio. Short-circuit current was recorded to evaluate specific chloride flux through CFTR channel. Western blot was used to evaluate CFTR maturation and COMMD1 expression. We demonstrate that CIGB-552 is non-toxic and preferentially enters CFTR-F508del expressing cells without modifying COMMD1 expression or localization in our cystic fibrosis cell models. CIGB-552 is not a potentiator nor a corrector but acts synergistically with Elexacaftor/Tezacaftor/Ivacaftor in improving chloride efflux and increasing transepithelial potential difference of CFTR-F508del cells. The mechanism implied by CIGB-552 with the COMMD1 protein in this positive effect are still undeciphered. CIGB-552 synergy with the tri-therapy to modulate CFTR-F508del function is still a promising strategy to improve cystic fibrosis treatment.