{
  "abstract": "Cystic fibrosis (CF) is a life-limiting autosomal recessive disorder caused by biallelic loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, most commonly F508del. Mutant CFTR disrupts transepithelial ion transport and intracellular redox homeostasis, leading to excessive accumulation of reactive oxygen species (ROS). Evidence from cohort studies, human airway organoid models, and single-cell transcriptomic analyses published between 2020 and 2026 has prompted substantial revision of the prevailing linear model of CF pathogenesis. These studies demonstrate that misfolded CFTR can independently initiate oxidative stress and low-grade inflammation in the absence of microbial colonization. Mitochondrial ROS (mitoROS) constitute a central signaling hub linking F508del-induced protein misfolding to transcriptional suppression of the Nrf2 antioxidant program, constitutive activation of the NLRP3 inflammasome, and dysregulation of TLR-cytokine cascades. Triple CFTR modulator regimens, including elexacaftor-tezacaftor-ivacaftor (ETI) and the once-daily combination vanzacaftor/tezacaftor/deutivacaftor (Alyftrek, FDA-approved December 2024 for patients ≥6 years carrying at least one F508del or other Alyftrek-responsive CFTR variant; pivotal SKYLINE 102/103 trials demonstrated non-inferiority versus ETI in largely ETI-eligible populations), have transformed clinical care. However, multi-omics data indicate that these agents do not fully restore airway redox homeostasis or resolve persistent low-grade inflammation, even when CFTR channel activity recovers to 40%–50% of wild-type levels. This incomplete recovery may reflect persistent epigenetic inflammatory memory, uncorrected mitochondrial dysfunction, and incomplete restoration of the non-channel functions of CFTR. Moreover, marked interindividual variability in modulator response and persistent nonresponse underscore the need for adjunctive strategies. This review integrates foundational mechanistic studies with recent findings to delineate how CFTR regulates ROS-dependent tissue injury and immune dysregulation and to assess redox-targeted combination therapies designed to complement CFTR modulator monotherapy.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Joint Surgery, Gansu Provincial Hospital, Lanzhou, China",
    "Ningxia Key Laboratory of Clinical Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, China",
    "Department of Pathology, General Hospital of Ningxia Medical University, Yinchuan, China",
    "Department of Burn Surgery, Gansu Provincial Hospital, Lanzhou, China",
    "Infectious Diseases Department, General Hospital of Ningxia Medical University, Yinchuan, China",
    "Department of Radiology, General Hospital of Ningxia Medical University, Yinchuan, China",
    "Engineering Technology Research Center of Traditional Chinese Medicine Prevention and Control of Common Diseases in Cattle and Sheep in Ningxia Hui Autonomous Region, Ningxia Vocational and Technical University (Ningxia Open University), Yinchuan, China"
  ],
  "article_type": "Review",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Cheng Shi"
    },
    {
      "affs": [
        1
      ],
      "name": "Minghui Zhang"
    },
    {
      "affs": [
        2
      ],
      "name": "Honghong Wang"
    },
    {
      "affs": [
        1
      ],
      "name": "Yumeng Jiao"
    },
    {
      "affs": [
        3
      ],
      "name": "Xuelian Wang"
    },
    {
      "affs": [
        4
      ],
      "name": "Yong Chen"
    },
    {
      "affs": [
        5
      ],
      "name": "Chunji Ma"
    },
    {
      "affs": [
        6
      ],
      "name": "Juan Shi"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/fmfd66eh3pyb6.bib",
  "cited_by": 0,
  "doi": "10.3389/fphar.2026.1979179",
  "fulltext_url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1979179/full",
  "id": "fmfd66eh3pyb6",
  "issns": [
    "1663-9812"
  ],
  "landing_url": "https://doi.org/10.3389/fphar.2026.1979179",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "feed-journal",
      "medicine/pharmacology-toxicology"
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      "lcc",
      "RM1-950"
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  "openalex": null,
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-04",
  "publisher": "Frontiers Media S.A.",
  "ris": "https://research.draconitic.com/paper/fmfd66eh3pyb6.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T14:21:05Z",
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  "subjects": [
    {
      "field": "medicine",
      "origin": "feed-journal:medicine/pharmacology-toxicology",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "CFTR regulation of ROS-mediated cellular injury and immune dysregulation in cystic fibrosis",
  "title_text": "CFTR regulation of ROS-mediated cellular injury and immune dysregulation in cystic fibrosis",
  "type": "peer-reviewed",
  "updated_at": "2026-11-05T14:21:01Z",
  "url": "https://research.draconitic.com/paper/fmfd66eh3pyb6",
  "venue": "Frontiers in Pharmacology",
  "versions": []
}