Pulmonary Arterial Hypertension Induces a Metabolic and Inflammatory Hepatopathy

Madelyn J. Blake; Sally E. Prins; Jeffrey C. Blake; Lynn M. Hartweck; Jenna B. Mendelson; Steeve Provencher; Sandra Breuils-Bonnet; Sebastien Bonnet; Kurt W. Prins

doi:10.1172/JCI201862

Pulmonary Arterial Hypertension Induces a Metabolic and Inflammatory Hepatopathy

Madelyn J. Blake,¹ Sally E. Prins,¹ Jeffrey C. Blake,² Lynn M. Hartweck,² Jenna B. Mendelson,³ Steeve Provencher,⁴ Sandra Breuils-Bonnet,⁴ Sebastien Bonnet,⁴ and Kurt W. Prins¹

Published May 28, 2026 - More info

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Abstract

BACKGROUND. Right ventricular failure (RVF) is a major determinant of mortality in pulmonary arterial hypertension (PAH), and hepatic dysfunction predicts adverse outcomes. However, the cell-specific effects of PAH/RVF on the human liver remain poorly defined. METHODS. We performed single-nucleus RNA sequencing of autopsy-derived liver tissue from 5 PAH patients and 4 non-PAH controls and compared these findings with publicly available single-nucleus RNA sequencing datasets from non-alcoholic steatohepatitis (NASH) and Fontan-associated liver disease (FALD). Transcriptomic analyses were integrated with histologic assessment, mitochondrial-enriched proteomics, and correlated with clinical markers of PAH/RVF severity. RESULTS. PAH livers showed cell-specific metabolic, inflammatory, and fibrotic remodeling distinct from NASH and FALD. PAH hepatocytes exhibited a hypoxia-adapted, Warburg-like metabolic phenotype with reduced fatty acid metabolism, gluconeogenesis, cytochrome P450 activity, and ketone metabolism. PAH endothelial cells demonstrated increased glycolytic pathway activity and disrupted adhesion/barrier signaling. PAH hepatic stellate cells displayed HIF-1 and PI3K-Akt pathway activation, and increased IL6 expression, which resulted in central vein fibrotic remodeling. PAH macrophages showed complement activation with reduced JAK-STAT signaling. Finally, HSC HIF-1 activity correlated with clinical markers of PAH/RVF severity. CONCLUSION. PAH induces a distinct metabolic and inflammatory hepatopathy characterized by hepatocyte metabolic reprogramming, HSC activation, and macrophage complement signaling. These findings support PAH-associated hepatopathy as a disease-specific end-organ phenotype linked to RVF severity.

Pulmonary Arterial Hypertension Induces a Metabolic and Inflammatory Hepatopathy

Madelyn J. Blake,¹ Sally E. Prins,¹ Jeffrey C. Blake,² Lynn M. Hartweck,² Jenna B. Mendelson,³ Steeve Provencher,⁴ Sandra Breuils-Bonnet,⁴ Sebastien Bonnet,⁴ and Kurt W. Prins¹

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Pulmonary Arterial Hypertension Induces a Metabolic and Inflammatory Hepatopathy

Madelyn J. Blake,1 Sally E. Prins,1 Jeffrey C. Blake,2 Lynn M. Hartweck,2 Jenna B. Mendelson,3 Steeve Provencher,4 Sandra Breuils-Bonnet,4 Sebastien Bonnet,4 and Kurt W. Prins1

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Madelyn J. Blake,¹ Sally E. Prins,¹ Jeffrey C. Blake,² Lynn M. Hartweck,² Jenna B. Mendelson,³ Steeve Provencher,⁴ Sandra Breuils-Bonnet,⁴ Sebastien Bonnet,⁴ and Kurt W. Prins¹