Kat5 deficiency in alveolar type II cells licenses STAT6-driven glycolytic reprogramming and pulmonary fibrosis.

Summary

This mechanistic study identifies a Kat5–STAT6 acetylation checkpoint that restrains STAT6 activation; its failure in fibrotic lungs drives HK2-mediated glycolytic reprogramming in ATII cells and matrix deposition. Restoring Kat5 in ATII cells re-acetylates STAT6 and ameliorates fibrosis in vivo, nominating Kat5 enhancers or STAT6 acetylation mimetics as therapeutic strategies.

Key Findings

• Kat5 directly acetylates STAT6 at K636, restraining dimerization, phosphorylation, and nuclear translocation.
• Reduced STAT6 K636 acetylation in fibrotic lungs leads to STAT6 hyperactivation and HK2-driven glycolytic reprogramming in ATII cells.
• ATII-specific restoration of Kat5 re-acetylates STAT6 and reduces fibrosis in vivo.
• Kat5-mediated STAT6 acetylation limits cooperation with profibrotic mediators (e.g., tPA), defining a therapeutic checkpoint.

Clinical Implications

While preclinical, the Kat5–STAT6 axis provides a tractable target for antifibrotic therapy—either by enhancing Kat5 function in ATII cells or mimicking STAT6 K636 acetylation to blunt profibrotic signaling.

Limitations

• Preclinical models; translational relevance to human therapeutic targeting requires validation.
• Specificity and safety of Kat5 activation or STAT6 acetylation mimetics in vivo are undefined.

Future Directions

Develop Kat5 activators or STAT6 K636 acetylation mimetics; test efficacy and safety in human-relevant models and early-phase trials; identify biomarkers (e.g., STAT6 acetylation status) for patient stratification.