Pulmonary arterial hypertension (PAH) is a rare but life-threatening disease that progressively narrows the blood vessels of the lungs, placing increasing strain on the heart and ultimately leading to heart failure. Although treatments have improved survival over the past two decades, PAH remains a major clinical challenge, with many patients facing poor long-term outcomes and limited treatment options.
A new review published online on June 17, 2026, in the Chinese Medical Journal examines how advances in molecular biology and translational research are reshaping scientists' understanding of PAH and driving the development of new therapies. The review was conducted by Dr. Taeil Yang of the Department of Cardiology, Gil Medical Center, Gachon University College of Medicine, Republic of Korea, and Professor Wook-Jin Chung of the Gachon Cardiovascular Research Institute, Gachon University, Republic of Korea.
"Over the past two decades, advances in molecular biology and translational science have reframed PAH as more than a vasoconstrictive disorder, revealing a complex interplay between endothelial dysfunction, immune activation, and metabolic reprogramming," says Prof. Chung.
To explore these advances, the authors reviewed findings from experimental studies, genetic research, translational investigations, and ongoing clinical trials. Their analysis highlights how scientists have moved beyond the traditional view of PAH as simply a disorder of narrowed blood vessels. Instead, PAH is increasingly recognized as a complex vascular remodeling disease in which endothelial dysfunction, chronic inflammation, metabolic dysregulation, and genetic susceptibility collectively drive progressive damage to the pulmonary circulation.
The review describes how dysfunction of endothelial cells, the cells that line blood vessels, can trigger abnormal vessel remodeling, causing the pulmonary arteries to gradually thicken and narrow. The researchers also emphasize the role of chronic inflammation, with immune cells such as T cells, B cells, and macrophages contributing to vascular injury and disease progression. In addition, cells within the pulmonary arteries undergo metabolic reprogramming, shifting from normal mitochondrial energy production toward a glycolysis-dominant, "Warburg-like" metabolic state that promotes excessive cell growth and resistance to programmed cell death.
Genetic discoveries have further transformed the field. Mutations in genes such as BMPR2, TBX4, and SOX17 have been linked to inherited and idiopathic forms of PAH. Many of these genes affect the bone morphogenetic protein (BMP)/transforming growth factor-beta (TGF-β) signaling pathway, which is now considered one of the central molecular pathways governing pulmonary vascular health. Disruptions in this pathway can impair vascular repair mechanisms and promote abnormal cell proliferation, making it a major focus of current research.
These insights are already shaping the next generation of treatments. While existing therapies mainly target pathways involved in blood vessel constriction, emerging approaches seek to address the underlying biological drivers of the disease. Among the most promising is sotatercept, which targets the BMP/TGF-β pathway. Researchers are also investigating therapies that target growth factor signaling, such as seralutinib, and inflammatory pathways, including tocilizumab and rituximab. Other approaches aim to correct metabolic abnormalities that contribute to disease progression.
The review also highlights large-scale multi-omics initiatives that are helping researchers better understand the biological differences among patients and advance precision medicine approaches that may enable treatments to be tailored to distinct molecular subtypes of PAH. By integrating genomics, transcriptomics, proteomics, metabolomics, and other high-dimensional datasets, researchers are working to identify disease-specific biomarkers and therapeutic targets that support more individualized care.
Prof. Chung explains, "Bridging basic discoveries with rigorously designed translational pipelines offers the most promising path toward reversing pulmonary vascular disease and improving long-term outcomes in PAH."
Overall, the review highlights how a deeper understanding of the biological mechanisms underlying PAH is transforming both research and treatment. By linking discoveries in genetics, inflammation, metabolism, and vascular biology with emerging therapeutic strategies, the field is moving toward more targeted approaches that could improve the lives of patients living with this devastating disease. As knowledge of the molecular drivers of PAH continues to expand, researchers are increasingly focused on developing disease-modifying therapies that not only relieve symptoms but also slow, halt, or potentially reverse pulmonary vascular remodeling.
Reference
DOI: https://doi.org/10.1097/CM9.0000000000004137
About Gachon University, Republic of Korea
Gachon University is a leading private university in the Republic of Korea, recognized for its commitment to innovation, research excellence, and interdisciplinary education. Located in Seongnam, near Seoul and the Pangyo Techno Valley—the university benefits from a dynamic environment that fosters collaboration between academia, healthcare, and industry. Through its colleges, research institutes, and affiliated medical centers, including Gil Medical Center, Gachon University conducts research across medicine, life sciences, engineering, and technology. The university is dedicated to advancing scientific discovery, translating research into clinical practice, and addressing global challenges through national and international partnerships.
Website: https://www.gachon.ac.kr/sites/eng/index.do
About Dr. Wook-Jin Chung from Gachon University College of Medicine, Republic of Korea
Dr. Wook-Jin Chung, MD, MS, PhD, FACC, is Professor of Cardiology at Gachon University College of Medicine and Director of the Gachon Cardiovascular Research Institute, Republic of Korea. With more than two decades of experience in cardiovascular medicine, his research focuses on pulmonary arterial hypertension, heart failure, and translational cardiovascular science. He has authored more than 140 peer-reviewed publications and holds five patents. Dr. Chung currently serves as President of the Korea Pulmonary Hypertension Society and Editor-in-Chief of Clinical Hypertension. He was a Visiting Associate Professor at Stanford University School of Medicine from 2011 to 2012.
