{
  "abstract": "Chronic inflammation is a major driver of lung damage in cystic fibrosis (CF), yet the molecular mechanisms that sustain this self-reinforcing inflammatory state remain incompletely understood. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD biosynthesis, can also act extracellularly (eNAMPT) as a pro-inflammatory mediator. Here, we investigated the relationship between NAMPT and matrix metalloproteinase-9 (MMP-9) in CF. Peripheral blood mononuclear cells (PBMCs) from people with CF (pwCF) displayed increased intracellular NAMPT and MMP-9 expression, together with enhanced AKT and ERK1/2 phosphorylation, compared with non-CF controls. Circulating eNAMPT levels were elevated in pwCF and positively correlated with MMP-9 levels. Although baseline eNAMPT levels were not significantly associated with FEV1% predicted, in a small longitudinal cohort, eNAMPT decreased following one year of elexacaftor/tezacaftor/ivacaftor (ETI) treatment, while FEV1% predicted increased in six of seven patients with paired measurements. In vitro, recombinant NAMPT increased MMP-9 expression and enzymatic activity in PBMCs from healthy donors. Pharmacological treatment with FK866 reduced endogenous eNAMPT release and attenuated NAMPT-induced MMP-9 production. Mechanistically, eNAMPT triggered rapid AKT activation followed by sustained ERK1/2 phosphorylation. Pharmacological inhibition of the MEK/ERK pathway attenuated NAMPT-induced MMP-9 activity, supporting a functional contribution of ERK1/2 signaling to NAMPT-mediated MMP-9 activation. Together, these findings identify a functional NAMPT–MMP-9 axis associated with inflammatory signaling in CF. Further studies are needed to establish its contribution to pulmonary inflammation and to determine the clinical significance of circulating eNAMPT in larger patient cohorts.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Experimental Medicine, University of Genoa, 16132 Genoa, Italy",
    "Department of Science and Technological Innovation, University of Eastern Piedmont, 15121 Alessandria, Italy",
    "Department of Clinical Sciences, Polytechnic University of Marche, 60126 Ancona, Italy",
    "Cystic Fibrosis Center, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy",
    "Research Laboratories, Research and Innovation Department (DAIRI), IRCCS AOU SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy",
    "Department of Agriculture, Food and Environmental Sciences, Polytechnic University of Marche, 60131 Ancona, Italy"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Laura Lori",
      "orcid": "0009-0004-8895-0074"
    },
    {
      "affs": [
        1
      ],
      "name": "Irene Fiorilla"
    },
    {
      "affs": [
        1
      ],
      "name": "Beatrice Ghezzi"
    },
    {
      "affs": [
        0
      ],
      "name": "Marco Pedrazzi",
      "orcid": "0000-0001-7289-884X"
    },
    {
      "affs": [
        1
      ],
      "name": "Alberto Maria Todesco"
    },
    {
      "affs": [
        2
      ],
      "name": "Francesca Mazzola",
      "orcid": "0000-0001-9140-012X"
    },
    {
      "affs": [
        0
      ],
      "name": "Roberta De Tullio",
      "orcid": "0000-0001-6925-3207"
    },
    {
      "affs": [
        3
      ],
      "name": "Federico Cresta",
      "orcid": "0000-0002-2483-5374"
    },
    {
      "affs": [
        3
      ],
      "name": "Carlo Castellani",
      "orcid": "0000-0003-1916-0963"
    },
    {
      "affs": [
        1,
        4
      ],
      "name": "Mauro Patrone",
      "orcid": "0000-0002-7740-2396"
    },
    {
      "affs": [
        5
      ],
      "name": "Nadia Raffaelli",
      "orcid": "0000-0002-4458-1789"
    },
    {
      "affs": [
        1,
        4
      ],
      "name": "Valentina Audrito",
      "orcid": "0000-0002-5660-4175"
    },
    {
      "affs": [
        0
      ],
      "name": "Monica Averna",
      "orcid": "0000-0002-9463-7533"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3cjxynaagq0xy.bib",
  "cited_by": 0,
  "doi": "10.3390/ijms27219496",
  "fulltext_url": null,
  "id": "3cjxynaagq0xy",
  "issns": [
    "1422-0067"
  ],
  "landing_url": "https://www.mdpi.com/1422-0067/27/21/9496",
  "language": null,
  "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": [
    [
      "openalex",
      "2740|Cystic Fibrosis Research Advances"
    ]
  ],
  "openalex": "W7224016099",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-24",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/3cjxynaagq0xy.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:57Z",
      "native_id": "10.3390/ijms27219496",
      "source": "crossref",
      "url": "https://www.mdpi.com/1422-0067/27/21/9496"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2740|Cystic Fibrosis Research Advances",
      "subfield": "general"
    }
  ],
  "title": "The NAMPT–MMP-9 Axis Contributes to Chronic Inflammation in Cystic Fibrosis",
  "title_text": "The NAMPT–MMP-9 Axis Contributes to Chronic Inflammation in Cystic Fibrosis",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:18:57Z",
  "url": "https://research.draconitic.com/paper/3cjxynaagq0xy",
  "venue": "International Journal of Molecular Sciences",
  "versions": []
}