International Journal of Molecular Medical Science, 2025, Vol.15, No.1, 20-32 http://medscipublisher.com/index.php/ijmms 22 is also significantly affected, with CF patients experiencing chronic low-grade inflammation and alterations in the gut microbiota. These changes are attributed to CFTR dysfunction, high-fat diets, and antibiotic use, which collectively impact growth, nutrition, and overall quality of life (Tam et al., 2022). Figure 1 Schematic view of common pathogenic events downstream of CFTR inhibition in Cystic Fibrosis (CF) and Celiac Disease (CD) (Adopted from Maiuri et al., 2019) Image caption: Loss-of-function mutations in the CFTR gene cause CFTR inhibition in CF. In the intestine from CD patients, the gliadin-derived P31-43 peptide interacts with, and binds to, specific residues of the NBD1 domain of CFTR, if the domain is in its inactive conformation, thus competing with ATP binding and blocking CFTR function. In both CF and CD epithelial cells, CFTR inhibition disrupts cellular proteostasis through two effects (i) transglutaminase-2 (TGM2) activation and (ii) BECN1 complex inhibition. In CD, TGM2 accessorily is recruited to a tripartite complex that stabilizes P31-43 binding to CFTR, thus worsening CFTR inhibition. In both conditions, CFTR inhibition leads to impaired endosomal trafficking, cytoskeleton disassembly, inflammasome activation resulting in interleukin-1β (IL1β) secretion, NF-κB activation and consequent interleukin-15 (IL15) production. Stressed enterocytes stimulate local inflammation in both CF and CD. In the gut from CD patients, this ignites the immune responses against gliadin, in particular P57-68, in a context of HLA-DQ2/DQ8. This pathogenic cascade can be interrupted by CFTR potentiators that prevent P31-43 binding to CFTR or by reconstitution of cellular proteostasis by TGM2 inhibition or BECN1 complex activation (Adopted from Maiuri et al., 2019) The endocrine system in CF patients shows altered glucocorticoid metabolism, with decreased activity of enzymes involved in cortisol metabolism and increased activity of enzymes converting cortisone to cortisol. This dysregulation may suggest adrenal insufficiency or HPA axis dysfunction, contributing to the overall metabolic imbalance observed in CF (Podgórski et al., 2022). The immune system is characterized by heightened ER stress and an overactive IRE1α-XBP1 pathway, leading to a hyper-metabolic state in immune cells such as macrophages, which exacerbates inflammation and metabolic dysfunction (Lara-Reyna et al., 2019). 3.2 Inflammation and infection as hallmarks of CF progression Inflammation and infection are central to the progression of CF, particularly in the lungs. The defective CFTR protein leads to impaired ion transport and dehydration of the airway surface liquid, creating a thick mucus layer that traps pathogens and promotes chronic bacterial infections. This environment triggers a robust inflammatory response dominated by neutrophils, which release proteases and reactive oxygen species, further damaging lung tissue (Mitri et al., 2020; Carmo et al., 2021). The persistent inflammation and infection cycle accelerates lung function decline and contributes significantly to CF morbidity and mortality (Costantini et al., 2020; Mason, 2024).
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