Publication | January 30, 2025
Lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension
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Read the PaperPulmonary arterial hypertension (PAH), a rare but serious condition characterized by abnormally high blood pressure in the lungs, is poorly understood and difficult to treat, carrying a high risk of mortality. Endothelial cell (EC) inflammation in the lungs is associated with PAH, but the molecular accelerators and brakes that regulate EC inflammation are incompletely described. PAH biomarkers are needed to elucidate disease mechanisms.
This landmark study published in Science – led by researchers at the University of Pittsburgh School of Medicine and for which Sapient provided mass spectrometry-based discovery metabolomics data – establishes causative linkages between lysosomal dysfunction and oxysterol metabolism, EC inflammation, and PAH.
Integrating large-scale genomics and nontargeted metabolomics datasets, the researchers were able to identify nuclear receptor coactivator 7 (NCOA7) as a primary controller of lysosomal activity and sterol homeostasis. NCOA7 deficiency in endothelium produced an oxysterol and bile acid signature via lysosomal dysfunction that promoted endothelial pathophentoypes, and this signature overlapped with a plasma metabolite signature associated with human PAH mortality.
The multi-omics study also found that single-nucleotide polymorphism (SNP) rs11154337 enhances NCOA7 expression to reduce inflammation in PAH, offering a mechanistic explanation of the genetic association between the SNP and PAH mortality, as well as the metabolomic association between the oxysterol signature and PAH severity.
Using computational modeling of small-molecule binding to NCOA7, the researchers were also able to synthesize an activator of NCOA7 that promoted lysosomal activity to put the ‘brake’ on oxysterol generation, which prevented EC immunoactivation and reversed PAH in a rodent model.
The identification of NCOA7 as a primary controller of PAH and discovery of metabolite signatures representing PAH biomarkers has broad implications for molecular diagnostic and therapeutic development.
To learn more, read the full paper and findings.
