Shared Metabolic Pathway Drives Cystic Fibrosis Lung Disease

A SHARED metabolic pathway may drive airway damage and persistent bacterial infections in people with cystic fibrosis.

New research has identified pyrimidine metabolism as a common mechanism linking abnormal airway cell growth with Pseudomonas aeruginosa persistence, offering potential therapeutic targets for cystic fibrosis lung disease.

Pyrimidine Metabolism Drives Cystic Fibrosis Lung Disease

Cystic fibrosis, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leads to progressive airway remodeling, including thickening and narrowing of the airways.

Researchers identified increased activity of the de novo pyrimidine synthesis pathway in CFTR-mutant airway epithelial cells. This metabolic adaptation compensates for impaired mitochondrial energy production but also stimulates abnormal cell proliferation, contributing to structural lung changes.

Experiments using primary human bronchial epithelial cells demonstrated that suppressing dihydroorotate dehydrogenase (DHODH), a key enzyme involved in pyrimidine production, reduced abnormal cell proliferation by approximately 75%.

Treatment with the DHODH inhibitor leflunomide similarly suppressed epithelial growth, while CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor normalized cell proliferation.

Bacterial Adaptation Sustains Lung Infections

The researchers also discovered that P. aeruginosa, a major cause of chronic cystic fibrosis lung infections, activates its own pyrimidine synthesis machinery to support bacterial growth and persistence.

In experimental models, bacteria adapted to the cystic fibrosis airway increased activity of the bacterial enzyme pyrD, enhancing nutrient utilization and bacterial biomass.

Disrupting pyrD substantially reduced bacterial burden. A pyrD-expressing, cystic fibrosis-adapted strain produced approximately 91-fold greater bacterial counts in lung tissue than comparator strains.

The metabolic changes also promoted alginate production and reduced inflammatory cytokine responses, creating conditions that supported airway remodeling and bacterial adaptation.

Potential New Targets for Cystic Fibrosis Treatment

These findings suggest that targeting pyrimidine metabolism could complement existing CFTR modulators and antimicrobial therapies.

However, inhibiting this pathway may also interfere with protective inflammatory regulation, potentially worsening airway injury during infection.

The researchers highlighted bacterial pyrimidine metabolism as a particularly promising target for future therapeutic development.

Although the findings were supported by human airway cells, sputum samples, and animal experiments, larger clinical studies are needed. The animal models also examined acute infection rather than the prolonged bacterial colonization characteristic of cystic fibrosis.

Further investigation could establish whether selectively disrupting bacterial metabolism can limit persistent infections while preserving airway integrity.

Reference
Lohia GK et al. Host-pathogen pyrimidine metabolism drives cystic fibrosis lung disease. Nat Commun. 2026. doi:10.1038/s41467-026-77940-z.

Featured Image: auremar on Adobe Stock.