The NAMPT–MMP-9 Axis Contributes to Chronic Inflammation in Cystic Fibrosis

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.