Regulation of lung progenitor plasticity and repair by fatty acid oxidation.

Summary

Using human IPF single-cell data, tissue staining, and AT2-targeted CPT1a perturbations in mice, the authors show that fatty acid oxidation preserves mitochondrial function and normal AT2 repair, restrains TGF-β signaling via SMAD7, and prevents basaloid/secretory intermediate states and fibrosis. CPT1a deficiency increases susceptibility to lung fibrosis with accumulation of aberrant epithelial intermediates.

Key Findings

• FAO gene expression is reduced in alveolar epithelial cells from IPF lungs (single-cell RNA-seq, tissue staining).
• CPT1a inhibition in AT2 cells induces mitochondrial dysfunction and basaloid/secretory marker acquisition with enhanced fibrosis susceptibility.
• CPT1a deficiency decreases SMAD7 and activates TGF-β signaling, promoting accumulation of aberrant epithelial intermediates.

Clinical Implications

Suggests that boosting FAO or restoring CPT1a function in AT2 cells could normalize repair and mitigate fibrosis in IPF, supporting metabolic-targeted interventions.

Limitations

• Preclinical models; no interventional human study demonstrating clinical benefit.
• Specificity to AT2-targeted CPT1a modulation requires translational safety/efficacy data.

Future Directions

Test FAO-enhancing or CPT1a-activating strategies in translational models and early-phase clinical trials; evaluate biomarkers (SMAD7/TGF-β activity, epithelial intermediates) to monitor response.