Abstract
Background
Portopulmonary Hypertension is a subtype of pulmonary arterial hypertension with high mortality. There are extremely few clinical trials to guide treatment in portopulmonary hypertension, which is typically based on the approach to treatment for other types of pulmonary arterial hypertension. Sotatercept, the newest pulmonary arterial hypertension approved therapeutic, is a novel activin signaling inhibitor which has been shown to significantly improve disease severity and enhance survival when added to background therapy in pulmonary arterial hypertension. Unfortunately, portopulmonary hypertension patients were excluded from the clinical trials that led to Sotatercept approval, and the efficacy, safety, and tolerability of Sotatercept in portopulmonary hypertension remains unclear.
Methods
Here we describe, to the best of our knowledge, a case report of the first use of Sotatercept in the treatment of portopulmonary hypertension, combined with single cell RNA sequencing and plasma proteomic analysis.
Results
We demonstrate that profiling the circulating leukocyte transcriptomic and circulating pulmonary artery proteomic signatures before and after Sotatercept treatment identifies changes in CD8 + T-Cell and Monocyte gene expression, and levels of proteins involved in inflammation and ubiquitination. Sotatercept appears well tolerated, effective in reducing pulmonary hypertension hemodynamic severity in a portopulmonary hypertension patient refractory to conventional pulmonary hypertension therapies, but may be associated with the development of hepatopulmonary syndrome.
Conclusions
This report demonstrates tolerability and efficacy of Sotatercept in portopulmonary hypertension, identifies candidate biomarkers of treatment response, but also suggests caution may be warranted. Findings from this work support further investigation of Sotatercept in the treatment of portopulmonary hypertension.
Plain language summary
Portopulmonary hypertension is disease of the blood vessels in the lungs that occurs in people with underlying liver disease. It is very deadly, there is no cure, and there are limited treatments. A new treatment for pulmonary hypertension, Sotatercept, has shown benefit, but has not yet been tried in patients with portopulmonary hypertension. Here we report the results of using Sotatercept in a patient with portopulmonary hypertension, who hadn’t fully responded to other pulmonary hypertension treatments. With Sotatercept, his disease improved, and he was able to get a liver transplant. He did develop low oxygen levels, that might have been related to Sotatercept treatment. This case highlights the possible risks and benefits of using Sotatercept in portopulmonary hypertension and encourages further study of Sotatercept for treatment of portopulmonary hypertension.
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Data availability
All single cell RNA sequencing data generated by this study have been deposited and are readily accessible in the NCBI Sequence Read Archive (PRJNA1322486, accessions SAMN51248041 and SAMN51248042). Proteomic data results are available in the Supplement. The source data for Table S1 is in Supplementary Data 1, the source data for Table S2 is in Supplementary Data 2, and the source data for Fig. S3 is in Supplementary Data 3 and the NCBI Sequence Read Archive files. The source data for Table 1, and Figs. 1, 2, and S1, S2 are in Supplementary Data 4. Additional data supporting the findings of this study are available from the corresponding author (AJ) upon reasonable request.
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Acknowledgements
This study was supported by a NIH/NHLBI grant (1K23HL16497-01A1) (AJ). The authors thank the patient who contributed his experience to this report.
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A.J., J.E., W.Z., A.Z. contributed to the conception and design of the research; A.J., W.Z., S.F., M.Y., A.Z. contributed to the acquisition, analysis, and interpretation of the data; A.J. drafted the manuscript; all authors critically revised the manuscript. A.J. agrees to be fully responsible for ensuring the integrity and accuracy of the work. All authors read and approved the final manuscript.
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Jose reports serving on the consultant or advisory board of Janssen and Merck. Elwing has received research grant support from Janssen, United Therapeutics, Liquidia, Gossamer Bio, Bayer, Merck, Altavant, Aerovate, Pulmovant, and serves on the consultant or advisory board of United Therapeutics, Altavant, Aerovate, Pulmovant, Bayer, Gossamer Bio, Liquidia, Merck, and Janssen. Jose and Ziady are co-inventors on a patent filing relating to this report (Provisional Application 63/876,188, filed 5 September 2025, Ohio, USA). The remaining authors (W.Z., S.F., M.Y.) have no competing interests to report.
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Jose, A., Zacharias, W., Fernandes, S. et al. Sotatercept for the treatment of portopulmonary hypertension: a case report. Commun Med (2026). https://doi.org/10.1038/s43856-026-01452-6
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DOI: https://doi.org/10.1038/s43856-026-01452-6
