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

Kato, Seiya; Hikita, Hayato; Tsukamoto, Osamu; Sato, Katsuhiko; Kamizono, Kohei; Sasaki, Yoichi; Fukumoto, Kenji; Myojin, Yuta; Murai, Kazuhiro; Tahata, Yuki; Makino, Yuki; Saito, Yoshinobu; Kodama, Takahiro; Motooka, Daisuke; Kobayashi, Shogo; Yokoi, Hideki; Mukoyama, Masashi; Kubota, Yoshiaki; Tatsumi, Tomohide; Eguchi, Hidetoshi; Takehara, Tetsuo

doi:https://doi.org/10.1053/j.gastro.2025.11.014

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

Kato, Seiya; Hikita, Hayato; Tsukamoto, Osamu et al.

Gastroenterology, 2026, 170(5), 1000-1016

Number of Access:57（2026-06-11 14:16 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/104612

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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
Creator	CreatorName Kato, Seiya
	NRID 1000020623044 1000020623044 ORCID 0000-0003-2488-7315 0000-0003-2488-7315 researchmap permalink hikitahayato hikitahayato Scopus Author ID 23667454900 23667454900 CreatorName Hikita, Hayato
	NRID 1000080589151 1000080589151 ORCID 0000-0002-9504-8001 0000-0002-9504-8001 researchmap permalink o_tsukamoto o_tsukamoto Scopus Author ID 7006371707 7006371707 CreatorName Tsukamoto, Osamu
	NRID 1000040838843 1000040838843 researchmap permalink KsatoK KsatoK CreatorName Sato, Katsuhiko
	CreatorName Kamizono, Kohei
	CreatorName Sasaki, Yoichi
	NRID 1000061011515 1000061011515 ORCID 0000-0002-8437-1153 0000-0002-8437-1153 researchmap permalink k.fukumoto k.fukumoto Scopus Author ID 57201500290 57201500290 CreatorName Fukumoto, Kenji
	NRID 1000020838817 1000020838817 ORCID 0000-0003-0360-9703 0000-0003-0360-9703 researchmap permalink yumyojin yumyojin Scopus Author ID 57211278135 57211278135 CreatorName Myojin, Yuta
	NRID 1000050867314 1000050867314 ORCID 0000-0001-8634-2922 0000-0001-8634-2922 researchmap permalink murai_kazuhiro murai_kazuhiro Scopus Author ID 57202460806 57202460806 CreatorName Murai, Kazuhiro
	NRID 1000000838047 1000000838047 ORCID 0000-0002-9116-7054 0000-0002-9116-7054 researchmap permalink yuki.tahata yuki.tahata Scopus Author ID 56755390400 56755390400 CreatorName Tahata, Yuki
	NRID 1000060771334 1000060771334 researchmap permalink yuki-makino yuki-makino Scopus Author ID 41561612200 41561612200 CreatorName Makino, Yuki
	NRID 1000060814598 1000060814598 ORCID 0000-0002-0624-0449 0000-0002-0624-0449 researchmap permalink saito_yoshinobu saito_yoshinobu Scopus Author ID 55912459300 55912459300 CreatorName Saito, Yoshinobu
	NRID 1000010623275 1000010623275 ORCID 0000-0002-6250-1324 0000-0002-6250-1324 researchmap permalink takahirokodama takahirokodama Scopus Author ID 35193885800 35193885800 CreatorName Kodama, Takahiro
	NRID 1000010636830 1000010636830 researchmap permalink daisukem daisukem Scopus Author ID 35315737900 35315737900 CreatorName Motooka, Daisuke
	CreatorName Kobayashi, Shogo
	NRID 1000090378779 1000090378779 CreatorName Yokoi, Hideki
	NRID 1000040270558 1000040270558 CreatorName Mukoyama, Masashi
	NRID 1000050348687 1000050348687 CreatorName Kubota, Yoshiaki
	NRID 1000020397699 1000020397699 researchmap permalink read0140669 read0140669 Scopus Author ID 7202112131 7202112131 CreatorName Tatsumi, Tomohide
	NRID 1000090542118 1000090542118 ORCID 0000-0002-2318-1129 0000-0002-2318-1129 researchmap permalink abcdabcdabcd abcdabcdabcd Scopus Author ID 7101627772 7101627772 CreatorName Eguchi, Hidetoshi
	NRID 1000070335355 1000070335355 CreatorName Takehara, Tetsuo
Subject	Mechanotransduction
Description	Kato Seiya, Hikita Hayato, Tsukamoto Osamu, 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 170, 1000 (2026); https://doi.org/10.1053/j.gastro.2025.11.014.
Abstract	Background & Aims: Chronic liver congestion progresses to liver fibrosis, eventually leading to cirrhosis and cancer. This study aimed to elucidate the mechanism of congestive hepatopathy (CH), focusing on liver sinusoidal endothelial cells (LSECs). Methods: Partial inferior vena cava ligation (pIVCL) was performed to induce hepatic congestion in mice. Single-cell RNA sequencing (scRNA-seq) was conducted on murine livers after pIVCL. Cells underwent hydrostatic pressure stimulation. scRNA-seq and spatial transcriptomics were performed on human livers from patients with Fontan-associated liver disease. Results: The scRNA-seq analysis showed that the integrin signaling pathway and yes-associated protein (YAP) were activated in pericentral LSECs after pIVCL. The most upregulated gene in pericentral LSECs was connective tissue growth factor (CTGF). Hydrostatic pressure activated YAP through integrin αV, leading to the upregulation of CTGF and type IV collagen (COL4) expression in LSECs. LSEC-derived CTGF upregulated the type I collagen (COL1) and COL4 expression in hepatic stellate cells. CTGF knockout in endothelial cells ameliorated CH-induced liver fibrosis and portal hypertension and even suppressed liver tumorigenesis. Integrin αV inhibition alleviated CH-induced liver fibrosis and portal hypertension with the decreased expression of CTGF, COL4, and COL1. scRNA-seq and spatial transcriptomics of clinical Fontan-associated liver disease samples revealed YAP activation and CTGF upregulation in pericentral LSECs, potentially leading to increased COL4 expression in LSECs and increased COL1 expression in hepatic stellate cells as fibrosis progressed. Conclusions: CTGF induction in LSECs may play an upstream role in the fibrogenesis of CH. The integrin αV–YAP–CTGF axis in LSECs could be a potential therapeutic target for CH.
Publisher	Elsevier BV
Source Title	Gastroenterology
Volume (Issue)	170(5)
Page	1000-1016
Date of Issued	2026-04-20
Language	English
Handle URL	https://hdl.handle.net/11094/104612
PISSN	00165085
eISSN	15280012
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1053/j.gastro.2025.11.014
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	Gastroenterology. 2026, 170(5), p. 1000-1016
DC.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
DC.creator	Kato, Seiya
	Hikita, Hayato
	Tsukamoto, Osamu
	Sato, Katsuhiko
	Kamizono, Kohei
	Sasaki, Yoichi
	Fukumoto, Kenji
	Myojin, Yuta
	Murai, Kazuhiro
	Tahata, Yuki
	Makino, Yuki
	Saito, Yoshinobu
	Kodama, Takahiro
	Motooka, Daisuke
	Kobayashi, Shogo
	Yokoi, Hideki
	Mukoyama, Masashi
	Kubota, Yoshiaki
	Tatsumi, Tomohide
	Eguchi, Hidetoshi
	Takehara, Tetsuo
DC.publisher	Elsevier BV
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2026-04-20
DC.identifier	https://doi.org/10.1053/j.gastro.2025.11.014
DC.subject	Mechanotransduction
DC.description	Kato Seiya, Hikita Hayato, Tsukamoto Osamu, 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 170, 1000 (2026); https://doi.org/10.1053/j.gastro.2025.11.014.
DCTERMS.abstract	Background & Aims: Chronic liver congestion progresses to liver fibrosis, eventually leading to cirrhosis and cancer. This study aimed to elucidate the mechanism of congestive hepatopathy (CH), focusing on liver sinusoidal endothelial cells (LSECs). Methods: Partial inferior vena cava ligation (pIVCL) was performed to induce hepatic congestion in mice. Single-cell RNA sequencing (scRNA-seq) was conducted on murine livers after pIVCL. Cells underwent hydrostatic pressure stimulation. scRNA-seq and spatial transcriptomics were performed on human livers from patients with Fontan-associated liver disease. Results: The scRNA-seq analysis showed that the integrin signaling pathway and yes-associated protein (YAP) were activated in pericentral LSECs after pIVCL. The most upregulated gene in pericentral LSECs was connective tissue growth factor (CTGF). Hydrostatic pressure activated YAP through integrin αV, leading to the upregulation of CTGF and type IV collagen (COL4) expression in LSECs. LSEC-derived CTGF upregulated the type I collagen (COL1) and COL4 expression in hepatic stellate cells. CTGF knockout in endothelial cells ameliorated CH-induced liver fibrosis and portal hypertension and even suppressed liver tumorigenesis. Integrin αV inhibition alleviated CH-induced liver fibrosis and portal hypertension with the decreased expression of CTGF, COL4, and COL1. scRNA-seq and spatial transcriptomics of clinical Fontan-associated liver disease samples revealed YAP activation and CTGF upregulation in pericentral LSECs, potentially leading to increased COL4 expression in LSECs and increased COL1 expression in hepatic stellate cells as fibrosis progressed. Conclusions: CTGF induction in LSECs may play an upstream role in the fibrogenesis of CH. The integrin αV–YAP–CTGF axis in LSECs could be a potential therapeutic target for CH.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	104612
citation_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
citation_author	Kato, Seiya
	Hikita, Hayato
	Tsukamoto, Osamu
	Sato, Katsuhiko
	Kamizono, Kohei
	Sasaki, Yoichi
	Fukumoto, Kenji
	Myojin, Yuta
	Murai, Kazuhiro
	Tahata, Yuki
	Makino, Yuki
	Saito, Yoshinobu
	Kodama, Takahiro
	Motooka, Daisuke
	Kobayashi, Shogo
	Yokoi, Hideki
	Mukoyama, Masashi
	Kubota, Yoshiaki
	Tatsumi, Tomohide
	Eguchi, Hidetoshi
	Takehara, Tetsuo
citation_publisher	Elsevier BV
citation_language	English
citation_date	2026-04-20
citation_journal_title	Gastroenterology
citation_volume	170
citation_issue	5
citation_firstpage	1000
citation_lastpage	1016
citation_doi	https://doi.org/10.1053/j.gastro.2025.11.014
citation_public_url	https://hdl.handle.net/11094/104612

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

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