Exosomes derived from bone marrow mesenchymal stem cells alleviate sepsis-induced ARDS via inhibition of HOXA9-mediated glycolysis in alveolar macrophages

Pulmonary injury in sepsis often develops into acute respiratory distress syndrome (ARDS), in which the polarization state of alveolar macrophages (AMs) is a central pathogenic factor. Bone marrow mesenchymal stem cell-derived exosomes (BMSCs-exo) have demonstrated therapeutic potential in septic ARDS through metabolic modulation, yet the specific mechanisms remain unclear. This study investigated whether BMSCs-exo attenuate ARDS by regulating AM polarization via glycolysis inhibition and clarified the role of HOXA9. BMSCs were identified using flow cytometry and trilineage differentiation. BMSCs-exo were characterized by transmission electron microscopy, nanoparticle tracking analysis and Western blot. An in vitro septic model was established by stimulating MH-S cells with lipopolysaccharide (LPS, 1 µg/mL). In vivo, ARDS was induced in C57BL/6 mice using either LPS (10 mg/kg) or cecal ligation and puncture (CLP), followed by caudal vein injection of BMSCs-exo. Glycolysis and macrophage polarization were evaluated with Western blot, RT-qPCR, and immunofluorescence. BMSCs-exo treatment improved survival in septic mice, alleviated pulmonary inflammation and edema, suppressed glycolysis in AMs, and restored M1/M2 balance. In vitro, BMSCs-exo downregulated glycolysis-associated markers in LPS-stimulated MH-S cells, suppressed M1 polarization, and facilitated M2 polarization. Notably, knockdown of the HOXA9 gene significantly diminished the ability of BMSCs-exo to suppress glycolysis and M1 polarization in MH-S cells. BMSCs-exo mitigate sepsis-induced ARDS by inhibiting HOXA9-mediated glycolysis and re-establishing AM polarization homeostasis, supporting their potential as a promising therapeutic approach for ARDS.