Stimulating the Heat Shock Response to Enhance Functional Recovery of F508del-CFTR

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the CFTR gene, with p.F508del being the most common mutation. This mutation results in protein misfolding, degradation, as well as impaired chloride channel function, leading to severe clinical symptoms. Despite significant advancements in CF therapy (modulators targeting F508del-CFTR, Trikafta), current treatments remain suboptimal, highlighting the need for improved therapeutic strategies. This project aims to identify molecular mechanisms that can restore F508del- CFTR function by testing various compounds on CFBE cells (an immortalized human bronchial cell line obtained from an F508del-CFTR homozygous patient that stably overexpresses F508del-CFTR). Specifically, we will explore the hypothesis that improved chaperone function would facilitate the functional rescue of F508del-CFTR. CFBE cells were treated with increasing doses of Eupalinolide A (Eup), a natural compound known to induce the the expression of HSP70 via the activation of HSF1 by inhibiting the interaction between HSF1 and HSP90. The results demonstrate that Eup treatment effectively increase the functional F508del-CFTR rescue induced by correctors. The molecular mechanism of Eup effect is here investigated. These findings suggest that targeting the chaperone system with compounds like Eup may represent a promising adjunct strategy to improve current therapies for patients with cystic fibrosis carrying the F508del mutation.