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. 2025 Oct;480(10):5521-5529.
doi: 10.1007/s11010-025-05331-x. Epub 2025 Jun 25.

Elexacaftor/tezacaftor/ivacaftor (ETI) therapy modifies the expression of interferon beta and inflammatory genes in the airways of adult patients with cystic fibrosis: a pilot study

Camilla Bitossi  1 , Federica Frasca  2 , Alessandra D'Auria  2 , Matteo Fracella  2 , Giulia Radocchia  3 , Maria Trancassini  3 , Laura Petrarca  4 , Domenico La Regina  4 , Patrizia Troiani  5 , Massimo Gentile  2 , Valeria Pietropaolo  3 , Fabio Midulla  4 , Giuseppe Cimino  5 , Guido Antonelli  2   6 , Alessandra Pierangeli  2 , Carolina Scagnolari  2   7
Affiliations

Elexacaftor/tezacaftor/ivacaftor (ETI) therapy modifies the expression of interferon beta and inflammatory genes in the airways of adult patients with cystic fibrosis: a pilot study

Camilla Bitossi et al. Mol Cell Biochem. 2025 Oct.

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies have revolutionized the treatment of cystic fibrosis (CF) by targeting the underlying protein defect. Investigating how elexacaftor/tezacaftor/ivacaftor (ETI) therapy affects interferon (IFN) signalling and inflammatory cytokine production in CF airway epithelial cells may clarify its role in alleviating the dysregulated innate immune response. Clinical efficacy was evaluated in 26 modulator-naive CF patients with at least one F508del mutation before and after 3 and 6 months of ETI treatment. Type I/III IFNs, IFNLR1, IFN-stimulated genes (ISG15, ISG56), interleukin 8 (IL-8) and IL-1β mRNA levels were analysed by RT real-time PCR in CF airway samples (n = 74). Patients showed significant improvements in pulmonary function (ppFEV1, 3 months: 12.5%, 6 months: 17.6%), BMI (3 months: 0.9 kg/m2, 6 months: 1.4 kg/m2), and sweat chloride (3 months: - 32.1 mEq/L, 6 months: - 44.4 mEq/L) compared to baseline (all p ≤ 0.001). The total number of exacerbations was also reduced (p = 0.002). Increased levels of IFNβ (p < 0.001) were found after 6 months of ETI therapy, whilst ISG15 and ISG56 decreased significantly (p = 0.022, p = 0.004). After 3 months, CF patients produced reduced levels of IL-8 and IL-1β (p = 0.001, p = 0.011) and even significantly lower levels after 6 months (p < 0.001, p < 0.001). ETI treatment appears to restore IFNβ expression and reduce levels of inflammatory genes (ISGs, IL-8 and IL-1β) in the airways, highlighting the potential of ETI to improve the dysregulated inflammatory status in CF.

Keywords: CFTR modulator therapies; Cystic fibrosis; ETI; IFN beta; IFN lambda; IL-1β; IL-8; ISG15 and ISG56; Inflammation.

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Conflict of interest statement

Declarations. Competing interests: The authors have no competing interests, as defined by Springer, or other interests that might be perceived as influencing the results and/or discussion reported in this paper. Ethical approval: The study was approved by the ethics committee of the Policlinico Umberto I Hospital (Rif. 5223), Sapienza University of Rome, and informed consent was obtained from patients suffering from CF.

Figures

Fig. 1
Fig. 1
A–D Gene expression levels of type I (IFNα, IFNβ, IFNε) (A) and type III (IFNλ1, IFNλ2/3) IFNs, the type III IFN receptor IFNLR1 (also known as IL28R1) (B), the IFN-stimulated genes, ISG15 and ISG56 (C), interleukin 8 (IL-8) and interleukin-1 beta (IL-1β) (D) in cells from respiratory samples of patients with cystic fibrosis (CF) before the start of ETI therapy (n = 26, T0), 3 months after the start of therapy (n = 26, T3) and 6 months after the start of therapy (n = 22, T6). *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001, ****p ≤ 0.0001 using Wilcoxon signed rank test
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