The histone demethylase KDM6B links obstructive sleep apnea to idiopathic pulmonary fibrosis.

Summary

KDM6B expression is elevated in human IPF lungs and experimental models, and intermittent hypoxia further amplifies its expression and profibrotic programs. Pharmacologic inhibition of KDM6B attenuated fibrosis, reduced myofibroblast activation and migration, and downregulated NOX4 and oxidative stress, positioning KDM6B as a tractable target linking OSA to IPF progression.

Key Findings

• KDM6B expression is increased in IPF lungs, bleomycin-treated mice, and TGF-β1–stimulated myofibroblasts.
• Intermittent hypoxia exacerbates fibrosis and myofibroblast activation and further upregulates KDM6B in vivo and in vitro.
• Pharmacologic inhibition of KDM6B reduces fibrosis, fibroblast activation/migration, and NOX4-driven oxidative stress.

Clinical Implications

If translated, KDM6B inhibition could mitigate fibrosis progression in IPF, particularly in patients with coexisting OSA. It also strengthens the rationale for aggressive diagnosis and treatment of OSA in fibrotic lung disease.

Limitations

• Preclinical models; clinical efficacy and safety of KDM6B inhibition remain untested.
• The specificity of KDM6B targeting and potential off-target epigenetic effects need careful evaluation.

Future Directions

Translate KDM6B inhibition into early-phase trials in fibrotic lung disease (with and without OSA), define patient selection biomarkers (e.g., KDM6B/NOX4 signatures), and explore combinatorial strategies with antifibrotics and OSA treatment.