{"id":9439,"date":"2026-02-27T19:00:08","date_gmt":"2026-02-27T10:00:08","guid":{"rendered":"https:\/\/www.med.osaka-u.ac.jp\/eng\/?page_id=9439"},"modified":"2026-03-02T09:50:57","modified_gmt":"2026-03-02T00:50:57","slug":"hikita2026-2-26","status":"publish","type":"page","link":"https:\/\/www.med.osaka-u.ac.jp\/eng\/activities\/results\/2025year\/hikita2026-2-26","title":{"rendered":"Seiya Kato, Hayato Hikita, Tetsuo Takehara \u226aGastroenterology and Hepatology\u226b <span>Activation of the integrin \u03b1V\u2013YAP\u2013CTGF axis in liver sinusoidal endothelial cells promotes liver fibrogenesis, leading to portal hypertension and liver carcinogenesis in congestive hepatopathy<\/span>"},"content":{"rendered":"<ul class=\"linkBar clearfix\">\n<li><a href=\"https:\/\/www.med.osaka-u.ac.jp\/activities\/results\/2025year\/hikita2026-2-26\">Text in Japanese<\/a><\/li>\n<\/ul>\n<p><em><i>Gastroenterology<\/i><\/em><\/p>\n<p><em>Researchers from The University of Osaka find that chronic liver congestion is linked to severe liver diseases through a specific signaling pathway<\/em> <em>in liver sinusoidal endothelial cells \u2013 key cells lining the liver\u2019s tiny blood vessels<\/em><\/p>\n<p class=\"figure\"><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-9436 size-medium\" src=\"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2025\/12\/hikitakatou2025en_fig1-400x232.png?_t=1764898484\" alt=\"\" width=\"400\" height=\"232\" srcset=\"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2025\/12\/hikitakatou2025en_fig1-400x232.png 400w, https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2025\/12\/hikitakatou2025en_fig1-1024x594.png 1024w, https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2025\/12\/hikitakatou2025en_fig1-768x445.png 768w, https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2025\/12\/hikitakatou2025en_fig1.png 1299w\" sizes=\"(max-width: 400px) 100vw, 400px\" \/><br \/>Fig1: Mechanical responses of liver sinusoidal endothelial cells to hepatic congestion.<br \/>License\uff1aOriginal content.<br \/>Usage restriction: \u00a0Credit must be given to the creator.<br \/>Credit: Seiya kato<\/p>\n<p>The long-term stasis of blood in the liver, known as chronic liver congestion, can lead to a range of diseases \u2013 some of which are fatal. However, identifying how liver congestion causes these diseases has remained unclear, causing difficulty in proposing the best treatment pathway.<\/p>\n<p>In a study recently published in <em><i>Gastroenterology<\/i><\/em>, Japanese researchers have identified a molecular pathway connecting liver congestion to liver fibrosis, portal hypertension, and liver tumorigenesis. This finding has important implications for potential therapies.<\/p>\n<p>Chronic liver congestion is also known as congestive hepatopathy, and often progresses to liver fibrosis, eventually cirrhosis, and even cancer. Despite these associations being well-established in the literature for a long time, the specific molecular mechanisms that link liver congestion with liver fibrosis remain relatively unknown.<\/p>\n<p>To change this, researchers at The University of Osaka decided to explore these mechanisms to search for potential therapeutic targets that may prevent liver congestion from developing into more severe diseases.<\/p>\n<p>\u201cWe focused on a type of liver cell called liver sinusoidal endothelial cells, or LSECs, which form the inner lining of the tiny blood vessels inside the liver and are directly affected when blood flow is blocked or slowed, such as during liver congestion,\u201d says lead author, Seiya Kato. \u201cWe used state-of-the-art techniques \u2013 single-cell and spatial transcriptomics, which allow us to analyze gene activity in individual cells and their locations within tissues \u2013 to study liver samples from a mouse model of congestion and from patients with conditions such as Fontan-associated liver disease. This helped us to uncover how liver congestion triggers changes at the molecular level.\u201d<\/p>\n<p>These analyses revealed increased activity of two key molecules involved in cell signaling in LSECs: Yes-associated protein (YAP) and connective tissue growth factor (CTGF). Interestingly, the integrin pathway was also observed to be activated in the mouse model of liver congestion. Using LSECs grown in the laboratory, the research team demonstrated that increased hydrostatic pressure (like that which occurs during chronic liver congestion) activates YAP through integrin \u03b1V, thereby upregulating CTGF. The team also revealed that inhibiting integrin \u03b1V or knocking out CTGF in LSECs leads to improved outcomes in the mouse model of liver congestion.<\/p>\n<p>How do these results apply to humans? In single-cell and spatial transcriptomic analyses of liver samples from patients with chronic liver congestion, the researchers found the same pattern that they had seen in mice. YAP was activated in LSECs, leading to increased CTGF levels, and these changes are thought to contribute to disease progression.<\/p>\n<p>\u201cOverall, we discovered that a signaling pathway \u2013 the integrin \u03b1V\u2013YAP\u2013CTGF pathway \u2013 in specialized liver blood vessel cells appears to connect liver congestion to fibrosis,\u201d \u201cThis newly identified pathway could offer a new direction for treatment.\u201d<\/p>\n<p>Given that chronic liver congestion can eventually cause serious conditions, such as liver fibrosis, portal hypertension, and liver cancer, these findings may have wide-reaching clinical benefits. Importantly, liver congestion is seen in people with congenital heart disease who have undergone the Fontan procedure, putting them at risk of congestion-related liver damage. Moreover, the increased pressure within the liver\u2019s tiny blood vessels that occurs during chronic liver congestion also happens in liver cirrhosis. This means that the discoveries in this study could help to inform the development of new treatments not only for patients with congestion-related liver disease, but also for those with liver cirrhosis caused by other conditions.<\/p>\n<p>###<\/p>\n<p>The article, \u201cActivation of the integrin \u03b1V\u2013YAP\u2013CTGF axis in liver sinusoidal endothelial cells promotes liver fibrogenesis, leading to portal hypertension and liver carcinogenesis in congestive hepatopathy,\u201d was published in <em><i>Gastroenterology<\/i><\/em> at DOI: <a href=\"https:\/\/doi.org\/10.1053\/j.gastro.2025.11.014\">https:\/\/doi.org\/10.1053\/j.gastro.2025.11.014<\/a><\/p>\n<p><strong>Summary:<br \/><\/strong>Researchers from The University of Osaka have found that a specific signaling pathway, the integrin \u03b1V\u2013YAP\u2013CTGF axis, may be associated with the development of liver fibrosis, portal hypertension, and liver cancer in patients with chronic liver congestion. These findings have important implications for the development of therapies aimed at preventing more severe forms of liver disease.<\/p>\n<p><strong>Tweet:<br \/><\/strong>Researchers from @UOsaka have studied mice and human patients to identify the missing link between chronic liver congestion and more severe liver disease: the integrin \u03b1V\u2013YAP\u2013CTGF signaling axis<br \/>@UOsaka<\/p>\n<p><strong>Primary Keyword: <\/strong>Health and medicine<\/p>\n<p><strong>Additional Keyword:<br \/><\/strong>Drug targets, molecular targets, liver damage, liver cancer, signaling cascades, signaling pathways, integrin signaling, pathophysiology, cell pathology<\/p>\n<p><strong>Method of Research:<\/strong>Experimental study<\/p>\n<p><strong>Subject of Research:<\/strong> Animals<\/p>\n<p class=\"figure\"><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-9437 size-medium\" src=\"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2025\/12\/hikitakatou2025en_fig2-400x204.png?_t=1766019054\" alt=\"\" width=\"400\" height=\"204\" srcset=\"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2025\/12\/hikitakatou2025en_fig2-400x204.png 400w, https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2025\/12\/hikitakatou2025en_fig2-1024x522.png 1024w, https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2025\/12\/hikitakatou2025en_fig2-768x391.png 768w, https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2025\/12\/hikitakatou2025en_fig2.png 1299w\" sizes=\"(max-width: 400px) 100vw, 400px\" \/><br \/>Figure 2\uff1a CTGF knockout in endothelial cells or pharmacological inhibition of integrin \u03b1V attenuates disease progression induced by hepatic congestion.<\/p>\n<p class=\"figure\"><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-9438 size-medium\" src=\"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2025\/12\/hikitakatou2025en_fig3-400x240.png?_t=1766019554\" alt=\"\" width=\"400\" height=\"240\" srcset=\"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2025\/12\/hikitakatou2025en_fig3-400x240.png 400w, https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2025\/12\/hikitakatou2025en_fig3-768x460.png 768w, https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2025\/12\/hikitakatou2025en_fig3.png 850w\" sizes=\"(max-width: 400px) 100vw, 400px\" \/><br \/>Figure 3\uff1a Single-cell and spatial transcriptomic analyses of Fontan-associated liver disease (FALD).<\/p>\n<p>&nbsp;<\/p>\n<p><strong>Title\uff1a<\/strong>\u201cActivation of the integrin \u03b1V\u2013YAP\u2013CTGF axis in liver sinusoidal endothelial cells promotes liver fibrogenesis, leading to portal hypertension and liver carcinogenesis in congestive hepatopathy\u201d<\/p>\n<p><strong>Journal\uff1a<\/strong><em><i>Gastroenterology<\/i><\/em><\/p>\n<p><strong>Authors\uff1a<\/strong>Seiya Kato, Hayato Hikita, Osamu Tsukamoto, Katsuhiko Sato, Kohei Kamizono, Yoichi Sasaki, Kenji Fukumoto, Yuta Myojin, Kazuhiro Murai, Yuki Tahata, Yuki Makino, Yoshinobu Saito, Takahiro Kodama, Daisuke Motooka, Shogo Kobayashi, Hideki Yokoi, Masashi Mukoyama, Yoshiaki Kubota, Tomohide Tatsumi, Hidetoshi Eguchi and Tetsuo Takehara<\/p>\n<p><strong>DOI\uff1a<\/strong><a href=\"http:\/\/10.1053\/j.gastro.2025.11.014\">10.1053\/j.gastro.2025.11.014<\/a><\/p>\n<p><strong>Funded by\uff1a<\/strong>Japan Agency for Medical Research and Development<\/p>\n<p><strong>Article publication date:<\/strong> 27-FEB-2026<\/p>\n<p><strong>Related links:<br \/><\/strong>Hayato Hikita<br \/><a href=\"https:\/\/rd.iai.osaka-u.ac.jp\/en\/b23b5f0ae68a066b.html\">https:\/\/rd.iai.osaka-u.ac.jp\/en\/b23b5f0ae68a066b.html<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"<p>Text in Japanese Gastroenterology Researchers from The University of Osaka find that chronic liver congestion  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