A groundbreaking study from researchers at The University of Osaka has unveiled a molecular cascade that elucidates the enigmatic progression from chronic liver congestion to severe hepatic diseases, including fibrosis, portal hypertension, and even liver carcinogenesis. Chronic liver congestion, often clinically recognized as congestive hepatopathy, describes the pathological stagnation of blood within the liver vasculature, eventually precipitating a spectrum of brutal liver ailments. Despite decades of clinical observations linking congestion to liver scarring and malignancy, the precise intracellular mechanisms remained elusive until now.
This insightful investigation, freshly published in the prestigious journal Gastroenterology, leverages cutting-edge single-cell and spatial transcriptomics to dissect liver tissue from both a murine model simulating hepatic congestion and patients with Fontan-associated liver disease—a congenital heart condition predisposing to chronic hepatic blood pooling. This dual model approach enabled unprecedented resolution of cellular alterations, particularly in a specialized cohort of cells known as liver sinusoidal endothelial cells (LSECs). These cells, constituting the delicate inner lining of hepatic microvasculature, are front-line responders to hemodynamic changes, sensitively modulating vascular tone, permeability, and fibrotic signaling.
The study identifies a pivotal regulatory axis involving integrin αV, Yes-associated protein (YAP), and connective tissue growth factor (CTGF) within LSECs as a critical driver of fibrogenesis under conditions of sustained hepatic congestion. Elevated intravascular pressure, a hallmark of congestion, mechanically activates integrin αV on LSECs, triggering translocation and activation of YAP—a transcriptional coactivator renowned for its role in mechanotransduction and tissue remodeling. Subsequent upregulation of CTGF by YAP amplifies fibrogenic signaling pathways, effectively linking mechanical stress to the molecular orchestration of extracellular matrix deposition and vascular remodeling.
Crucially, intervention experiments demonstrated that inhibition of integrin αV markedly attenuates YAP activation and CTGF expression, thereby mitigating liver fibrosis in the congested murine model. Parallel experiments deploying targeted knockout models confirmed that abolishing CTGF in LSECs disrupts this pathological signaling, resulting in significant restoration of hepatic architecture and function. These findings provide compelling evidence that the integrin αV–YAP–CTGF signaling cascade is not only necessary but sufficient to drive fibrosis and its downstream complications in congestive hepatopathy.
Translating these murine insights to the human condition, the team applied the same single-cell and spatial transcriptomic methodology to liver biopsies from patients suffering chronic liver congestion. Strikingly, they observed a conserved activation pattern of the integrin αV–YAP–CTGF axis within human LSECs, reinforcing the clinical relevance of their findings. This molecular signature potentially offers a novel biomarker for early detection and severity stratification of congestion-related liver disease.
These revelations bear profound implications for the millions affected by chronic liver congestion worldwide, including patients post-Fontan procedure—a palliative operation for complex congenital heart defects that leaves individuals vulnerable to congestion-induced hepatic injury. Moreover, elevated sinusoidal pressure is a common feature not only in congestive hepatopathy but also in cirrhotic liver diseases of diverse etiologies, suggesting that therapeutic targeting of the integrin αV–YAP–CTGF pathway could revolutionize treatment paradigms for a broad spectrum of liver conditions characterized by fibrosis and portal hypertension.
Embedding these findings within the broader context of hepatic pathophysiology, the research underscores the significance of mechanotransduction in the progression of liver diseases. While previous studies have implicated various fibrogenic mediators, the precise integration of mechanical stimuli with endothelial cellular responses offers a fresh and transformative perspective, challenging existing dogma and opening avenues for innovative pharmacological interventions.
Highlighting the methodological rigor, the researchers’ application of single-cell transcriptomics facilitated dissection of the heterogeneity among liver cell populations, isolating LSECs as the keystone in fibrosis initiation. Complementary spatial transcriptomic analysis preserved the anatomical context of gene expression, enabling correlation between molecular findings and histopathological changes. This integrative approach exemplifies the power of modern omics technologies in decoding complex cellular microenvironments driving disease processes.
Beyond identifying the integrin αV–YAP–CTGF pathway as a therapeutic target, the study suggests potential clinical interventions, including small-molecule inhibitors of integrin αV or agents modulating YAP activity. Such targeted therapies could halt or reverse fibrosis progression, ultimately preventing portal hypertension and hepatocellular carcinoma. However, clinical trials will be imperative to assess safety, efficacy, and optimal therapeutic windows, especially given the delicate balance of integrin and YAP functions in normal physiology.
In summary, this research from The University of Osaka not only demystifies the mechanistic bridge connecting chronic liver congestion to devastating hepatic complications but also shines a promising light on potential molecular targets for future therapies. The integrin αV–YAP–CTGF axis emerges as a linchpin in hepatic endothelial mechanotransduction pathways, offering hope for millions burdened by liver fibrosis and its sequelae.
Subject of Research: Animals
Article Title: Activation of the integrin αV–YAP–CTGF axis in liver sinusoidal endothelial cells promotes liver fibrogenesis, leading to portal hypertension and liver carcinogenesis in congestive hepatopathy
News Publication Date: 27-Feb-2026
Web References: http://dx.doi.org/10.1053/j.gastro.2025.11.014
References: Kato, S., Hikita, H., et al. Activation of the integrin αV–YAP–CTGF axis in liver sinusoidal endothelial cells promotes liver fibrogenesis, leading to portal hypertension and liver carcinogenesis in congestive hepatopathy. Gastroenterology. 2026.
Image Credits: Seiya Kato
Keywords: Liver fibrosis, Congestive hepatopathy, Liver sinusoidal endothelial cells, Integrin αV, YAP signaling, CTGF, Mechanotransduction, Portal hypertension, Liver cancer, Single-cell transcriptomics, Spatial transcriptomics, Mechanobiology
Tags: chronic liver congestion mechanismsCTGF role in hepatic fibrosisFontan-associated liver disease researchhepatic fibrogenesis targetsintegrin αV in liver fibrosisliver carcinogenesis prevention strategiesliver sinusoidal endothelial cells functionportal hypertension molecular pathwayssingle-cell transcriptomics in hepatologyspatial transcriptomics liver studiestherapeutic targets for severe liver diseaseYAP signaling in liver disease
