Researchers proposed that MLK3 pathway acts on CFTR proteostasis by modulating the levels of machinery controlling proteostasis and small molecules targeting this pathway signaling can be potent correctors of F508del-CFTR proteostasis. So they identified the molecular mechanisms of this pathway and also gave evidence of repositionable drugs targeting this pathway as correctors to rescue F508del-CFTR. In particular, about MLK3 pathway, they found Insulin-induced gene (INSIG-1) to be an essential downstream executor of the proteostasis control by MLK3 pathway, but it is possible to inhibit its mechanism making CFTR-F508del insensitive to its action. They also screened several clinically approved (or safety approved after crossing Phase I trials) MLK3 pathway inhibitors as potential correctors of F508del-CFTR proteostasis and found 3 active compounds that restored proteostasis of F508del-CFTR as measured by biochemical maturation assays. Finally, they evaluated the mechanism of action of RNF215, an uncharacterized ubiquitin ligase previously identified, and demonstrated its downregulation also potently restored the chloride conductance in the F508del-CFTR expression. These analyses provide insights into CF pathology; provide specific targets to control F508del-CFTR proteostasis and also efficient small molecules regulators that can rescue F508del-CFTR.