Histone methyltransferase KMT2A promotes pulmonary fibrogenesis via targeting pro-fibrotic factor PU.1 in fibroblasts.
Summary
This mechanistic study identifies KMT2A as an epigenetic driver of pulmonary fibrosis that upregulates PU.1 in fibroblasts via H3K4me3, thereby promoting fibrogenesis. Genetic knockdown, fibroblast-specific PU.1 deletion, and a KMT2A complex inhibitor (mm102) each attenuated bleomycin-induced fibrosis, nominating KMT2A→PU.1 as a targetable axis.
Key Findings
- KMT2A-positive fibroblasts are increased in IPF lungs and in bleomycin-injured mouse lungs.
- Fibroblast KMT2A knockdown and the KMT2A complex inhibitor mm102 attenuate bleomycin-induced pulmonary fibrosis.
- KMT2A upregulates PU.1 via H3K4me3 at the PU.1 promoter; fibroblast-specific PU.1 knockout reduces fibrosis.
Clinical Implications
Although preclinical, the data suggest KMT2A inhibition could complement current antifibrotics and that PU.1/H3K4me3 signatures may serve as biomarkers for patient stratification.
Why It Matters
Reveals a previously unrecognized epigenetic pathway driving IPF and provides pharmacologic proof-of-concept for targeting KMT2A. This could reorient antifibrotic drug discovery toward histone-modifying enzymes.
Limitations
- Bleomycin models may not fully recapitulate chronic human IPF pathobiology
- Selectivity and translational pharmacology of mm102 require further characterization
Future Directions
Develop selective KMT2A inhibitors with favorable PK/PD; validate PU.1/H3K4me3 signatures and KMT2A activity in longitudinal human IPF cohorts; assess combinatorial therapy with approved antifibrotics.
Study Information
- Study Type
- Case-control
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic evidence from animal models and ex vivo human tissues
- Study Design
- OTHER