Nat Commun. 2026 Mar 20;17(1):2655. doi: 10.1038/s41467-026-70193-w.

ABSTRACT

Pulmonary fibrosis represents a progressive interstitial lung disease marked by excessive extracellular matrix deposition and architectural distortion. Vascular endothelial cells critically contribute to fibrogenesis through paracrine secretion of pro-fibrotic mediators, yet their mechanobiological regulation remains elusive. Using integrated single-cell multi-omics profiling of human pulmonary fibrosis specimens and experimental fibrosis models induced by bleomycin or silica, we identify mechanosensitive Piezo1 upregulation in Endothelial cells as a hallmark of fibrotic progression. Endothelial-specific Piezo1 knockout significantly attenuates Bleomycin-induced fibrotic remodeling in male mice, establishing its pathogenic necessity. Mechanistically, PIEZO1 activation promotes pulmonary fibrosis development via CAPN2-mediated STAT3 phosphorylation, which may regulate the secretion of the pro-fibrotic molecule interleukin-33. These findings suggest that the endothelial PIEZO1-CAPN2-STAT3-IL33 axis is a potential therapeutic target for PF intervention.

PMID:41862476 | PMC:PMC13004862 | DOI:10.1038/s41467-026-70193-w

Redox Biol. 2026 Jan 14;92:104026. doi: 10.1016/j.redox.2026.104026. Online ahead of print.

ABSTRACT

Primary graft dysfunction (PGD) caused by ischemia-reperfusion injury (IRI) is a major complication after lung transplantation, yet its underlying mechanisms remain unclear. Triggering receptor expressed on myeloid cells 1 (Trem1) is an important mediator of inflammation, but its role in neutrophil function and metabolic reprogramming during lung IRI is not well understood. In this study, we used a murine orthotopic lung transplantation model with cold ischemia and reperfusion, and Trem1 knockout (Trem1-/-) and myeloid-specific Trem1 conditional knockout mice (Lysm^CreTrem1^fl) to explore the role of Trem1 in neutrophil recruitment, neutrophil extracellular trap (NET) formation, and metabolism. Our results show that Trem1 expression increases in both mouse and human lungs after reperfusion and correlates with neutrophil infiltration and lung injury. Trem1 deficiency significantly reduced neutrophil and macrophage recruitment, NET formation, and tissue damage. Multi-omics analysis revealed that Trem1 deletion suppressed oxidative phosphorylation (OXPHOS) and induced a metabolic shift in neutrophils toward glycolysis. In clinical samples, the abundance of TREM1+ neutrophils was correlated with PGD severity and OXPHOS activity. These findings identify Trem1 as a key regulator of neutrophil metabolism and recruitment in lung IRI, and suggest that targeting Trem1 may provide a novel therapeutic strategy to mitigate PGD and improve lung transplant outcomes.

PMID:41861599 | DOI:10.1016/j.redox.2026.104026