Hepatopulmonary syndrome (HPS) represents a complex manifestation of chronic liver disease, characterized by pulmonary angiogenesis and refractory hypoxemia. Despite its clinical significance, the pathophysiological mechanisms remain poorly understood. As a result, liver transplantation remains the only currently recognized definitive therapy, highlighting the need for pharmacological interventions targeting the underlying systemic metabolic and angiogenic dysfunction.

In this recent Genes & Diseases study, researchers from the First Affiliated Hospital (Southwest Hospital) of Army Medical University, Chongqing Traditional Chinese Medicine Hospital, the Seventh People's Hospital of Chongqing (The Affiliated Central Hospital of Chongqing University of Technology), and Université de Toulouse investigated the therapeutic potential of agrimoniin, a natural polyphenolic compound known for its hepatoprotective, anti-angiogenic, and metabolic regulatory properties, as an integrated strategy for simultaneously targeting liver injury and pulmonary complications associated with HPS, while specifically examining the interplay between oxidative phosphorylation, glycolytic flux, and vascular remodeling.

Using an experimental model of HPS established via common bile duct ligation, the study integrated transcriptome analysis with clinical data from ICU cohorts to elucidate the role of metabolic dysregulation in disease progression. The results showed that progressive liver disease is characterized by an imbalance between oxidative phosphorylation and glycolysis, with enhanced glycolytic activity being associated with poorer clinical outcomes, including respiratory complications and increased in-hospital mortality. These observations provide evidence that metabolic reprogramming is closely linked to disease progression, suggesting that regulating mitochondrial dysfunction and glycolysis may represent a promising therapeutic approach for HPS.

Additional experiments showed that HPS was associated with metabolic disturbances characterized by reduced mitochondrial oxidative phosphorylation, enhanced glycolytic flux, increased lactate production, and impaired energy homeostasis, which correlated with pathological pulmonary angiogenesis, deterioration of liver function, disruption of pulmonary architecture, and worsening hypoxemia. Agrimoniin treatment at 3 mg/kg/day and 8 mg/kg/day during the early stages of HPS significantly attenuated these pathological changes by restoring mitochondrial respiration, reducing glycolytic activity, improving oxygen utilization, and suppressing abnormal vascular proliferation within the lungs. Concurrent improvements in hepatic pathology further indicated that agrimoniin exerts a coordinated protective effect across both affected organs rather than acting only on pulmonary manifestations.

Mechanistically, the study utilized TCM suite analysis, molecular docking, and molecular dynamics simulations to identify PGC-1α as a primary molecular target of agrimoniin. Activation of PGC-1α by agrimoniin restored metabolic balance, effectively countering the glycolytic shift and limiting aberrant intrapulmonary vascular growth. Importantly, silencing PGC-1α markedly diminished the beneficial effects of agrimoniin on endothelial migration, tube formation, glycolytic flux, and mitochondrial respiration, demonstrating that activation of this transcriptional coactivator is essential for mediating the observed improvements in vascular remodeling and metabolic balance.

Overall, this study identifies agrimoniin as a promising candidate for integrated therapy in HPS by demonstrating its ability to improve liver and lung function through activation of PGC-1α, restoration of mitochondrial homeostasis, suppression of glycolysis, and inhibition of pathological angiogenesis. This research provides a significant advancement in the molecular understanding of HPS and offers a viable pathway for the development of pharmacotherapeutic interventions.

Reference
Title of the original paper: Agrimoniin ameliorates intrapulmonary angiogenesis and improves hypoxemia in hepatopulmonary syndrome via PGC-1α activation and glycolysis down-regulation
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101941

Funding Information:
National Natural Science Foundation of China (No. U25A2021, No. 82100658 and 82270656)
Science Foundation of Chongqing, China (No. cstc2019jcyj-msxmX0667)
Youth Top Talent Project of Chongqing Municipal Health Commission (China) (No. YXQN202434)
Key project of Chongqing Natural Science Foundation (China) (No. CSTB2023NSCQ-ZDX0003)
Science-Health Joint Medical Scientific Research Project of Chongqing, China (No. 2025MSXM012)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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