{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T19:52:52Z","timestamp":1791402772424,"version":"4.3.3"},"reference-count":48,"publisher":"American Society for Clinical Investigation","issue":"13","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":34,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01 HL158795,R01 HL162927,F31 HL170585"],"award-info":[{"award-number":["R01 HL158795,R01 HL162927,F31 HL170585"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,1]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>We performed single-nucleus RNA-seq (snRNA-seq) of autopsy-derived liver tissue from 5 patients with PAH and 4 healthy individuals (non-PAH) treated as controls and compared these findings with publicly available snRNA-seq datasets from nonalcoholic steatohepatitis (NASH) and Fontan-associated liver disease (FALD). Transcriptomic analyses were integrated with histologic assessment, mitochondrion-enriched proteomics, and correlations with clinical markers of PAH\/RVF severity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>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 altered adhesion\/barrier signaling. PAH hepatic stellate cells (HSCs) displayed HIF-1 and PI3K\/Akt pathway activation, increased IL-6 expression, and histologic evidence of perivascular fibrotic remodeling. PAH macrophages showed complement activation with reduced JAK\/STAT signaling. HSC HIF-1 activity correlated with clinical markers of PAH\/RVF severity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>PAH induces a distinct metabolic and inflammatory hepatopathy characterized by hepatocyte metabolic reprogramming, HSC activation, macrophage complement signaling, and suppressed ketone metabolism. These findings support PAH-associated hepatopathy as a disease-specific end-organ phenotype linked to RVF severity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>FUNDING<\/jats:title>\n                    <jats:p>NIH grants F31 HL170585, R01 HL158795, and R01 HL162927.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1172\/jci201862","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T17:51:37Z","timestamp":1779990697000},"source":"Crossref","is-referenced-by-count":2,"title":["Pulmonary arterial hypertension induces a metabolic and inflammatory hepatopathy"],"prefix":"10.1172","volume":"136","author":[{"given":"Madelyn J.","family":"Blake","sequence":"first","affiliation":[{"name":"Gazes Cardiac Research Institute, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, 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