PGC-1α mediates migrasome secretion accelerating macrophage-myofibroblast transition and contributing to sepsis-associated pulmonary fibrosis.

Summary

Using an LPS-induced SAPF mouse model and fibroblast–macrophage co-cultures, the authors show that PGC-1α suppression in lung fibroblasts triggers mitochondrial dysfunction and mtDNA-laden migrasome release, which initiates macrophage–myofibroblast transition and accelerates fibrosis. Pharmacologic activation of PGC-1α curtailed migrasome release, inhibited MMT, and attenuated SAPF, revealing a targetable fibroblast–immune crosstalk.

Key Findings

• LPS exposure suppressed PGC-1α in lung fibroblasts, causing mitochondrial dysfunction and cytosolic mtDNA accumulation.
• mtDNA-containing migrasomes released from fibroblasts initiated macrophage–myofibroblast transition and promoted fibrosis.
• Pharmacologic activation of PGC-1α reduced migrasome release, inhibited MMT, and alleviated SAPF in vivo.

Clinical Implications

While preclinical, the data suggest that enhancing PGC-1α signaling or blocking mtDNA-migrasome release could prevent or attenuate post-sepsis pulmonary fibrosis. Biomarker development (e.g., circulating migrasome mtDNA) may aid risk stratification after ARDS.

Limitations

• Sample sizes and detailed quantitative effect sizes are not provided in the abstract
• Translation to human SAPF remains untested; off-target effects of PGC-1α activation need evaluation

Future Directions

Validate migrasome/mtDNA biomarkers in ARDS survivors, and test PGC-1α modulators or migrasome pathway inhibitors in large-animal models and early-phase clinical trials.