GDF15 is associated with hepatocellular senescence and correlates with mortality in patients with alcohol-associated hepatitis

Background & Aims: Cellular senescence is characterized by the loss of proliferative capacity, cell cycle arrest, and the acquisition of a proinflammatory senescence-associated secretory phenotype (SASP). Senescence is frequently present in advanced chronic liver diseases; however, the impact of...

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Autores: Rubio-Tomás T, Martí-Aguado D, Blaya D, Ariño S, Aguilar-Bravo B, Martínez García de la Torre RA, Miravet-Marti M, Ferrer-Lorente R, Zanatto L, Xu Z, Garcia-Tercero L, Mateos-Sánchez C, Lozano JJ, Dotti I, Poisson J, Tanguy M, Salas A, Rautou PE, Bataller R, Sancho-Bru P
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2025
País:España
Recursos:INCLIVA
Repositório:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
OAI Identifier:oai:incliva.fundanetsuite.com:p20285
Acesso em linha:https://incliva.portalinvestigacion.com/publicaciones/20285
Access Level:Acceso aberto
Palavra-chave:alcohol-related liver disease
alcohol-associated hepatitis
senescence
GDF15
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spelling GDF15 is associated with hepatocellular senescence and correlates with mortality in patients with alcohol-associated hepatitisRubio-Tomás TMartí-Aguado DBlaya DAriño SAguilar-Bravo BMartínez García de la Torre RAMiravet-Marti MFerrer-Lorente RZanatto LXu ZGarcia-Tercero LMateos-Sánchez CLozano JJDotti IPoisson JTanguy MSalas ARautou PEBataller RSancho-Bru Palcohol-related liver diseasealcohol-associated hepatitissenescenceGDF15Background & Aims: Cellular senescence is characterized by the loss of proliferative capacity, cell cycle arrest, and the acquisition of a proinflammatory senescence-associated secretory phenotype (SASP). Senescence is frequently present in advanced chronic liver diseases; however, the impact of hepatocellular senescence in alcohol-associated liver disease (ALD) progression and alcohol-associated hepatitis (AH) is poorly understood. Methods: Senescence was evaluated in transcriptomic data from patients at different ALD stages: advanced fibrosis (n = 10), cirrhosis (n = 10), and AH (n = 29). Plasma GDF15 levels were tested in patients with AH (n = 68), compensated cirrhosis (n = 15), heavy drinkers without liver disease (n = 15), and healthy controls (n = 10). Results were confirmed in an independent validation cohort. Results: Transcriptomic analysis revealed an increased expression of senescence-associated genes and an enrichment of SASP gene signatures in patients with cirrhosis and particularly with AH. The association of senescence with AH was confirmed by p21 staining and the expression of senescence markers (i.e. CDKN1A, CDKN2A, CDKN2B, IL6, and SERPINE1), which positively correlated with clinical severity scores. Among the SASP factors, GDF15 was expressed in the hepatocytes of patients with AH and was strongly associated with senescence markers. Circulating GDF15 levels were specifically increased in patients with AH and positively correlated with severity scores. Moreover, plasma GDF15 levels predicted the response to corticosteroids and 90-day mortality in two independent cohorts of patients with AH. Conclusions: These results suggest that AH is characterized by the presence of hepatocellular senescence and elevated circulating levels of SASP factors, particularly GDF15, which correlates with patients' poor outcomes. This suggests that senescence may be both a player in AH pathogenesis and a potential biomarker for AH.<br /> (c) 2025 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).ELSEVIER2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://incliva.portalinvestigacion.com/publicaciones/20285JHEP ReportsISSN: 25895559reponame:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVAinstname:INCLIVAInglésinfo:eu-repo/semantics/openAccessoai:incliva.fundanetsuite.com:p202852026-06-07T16:35:31Z
dc.title.none.fl_str_mv GDF15 is associated with hepatocellular senescence and correlates with mortality in patients with alcohol-associated hepatitis
title GDF15 is associated with hepatocellular senescence and correlates with mortality in patients with alcohol-associated hepatitis
spellingShingle GDF15 is associated with hepatocellular senescence and correlates with mortality in patients with alcohol-associated hepatitis
Rubio-Tomás T
alcohol-related liver disease
alcohol-associated hepatitis
senescence
GDF15
title_short GDF15 is associated with hepatocellular senescence and correlates with mortality in patients with alcohol-associated hepatitis
title_full GDF15 is associated with hepatocellular senescence and correlates with mortality in patients with alcohol-associated hepatitis
title_fullStr GDF15 is associated with hepatocellular senescence and correlates with mortality in patients with alcohol-associated hepatitis
title_full_unstemmed GDF15 is associated with hepatocellular senescence and correlates with mortality in patients with alcohol-associated hepatitis
title_sort GDF15 is associated with hepatocellular senescence and correlates with mortality in patients with alcohol-associated hepatitis
dc.creator.none.fl_str_mv Rubio-Tomás T
Martí-Aguado D
Blaya D
Ariño S
Aguilar-Bravo B
Martínez García de la Torre RA
Miravet-Marti M
Ferrer-Lorente R
Zanatto L
Xu Z
Garcia-Tercero L
Mateos-Sánchez C
Lozano JJ
Dotti I
Poisson J
Tanguy M
Salas A
Rautou PE
Bataller R
Sancho-Bru P
author Rubio-Tomás T
author_facet Rubio-Tomás T
Martí-Aguado D
Blaya D
Ariño S
Aguilar-Bravo B
Martínez García de la Torre RA
Miravet-Marti M
Ferrer-Lorente R
Zanatto L
Xu Z
Garcia-Tercero L
Mateos-Sánchez C
Lozano JJ
Dotti I
Poisson J
Tanguy M
Salas A
Rautou PE
Bataller R
Sancho-Bru P
author_role author
author2 Martí-Aguado D
Blaya D
Ariño S
Aguilar-Bravo B
Martínez García de la Torre RA
Miravet-Marti M
Ferrer-Lorente R
Zanatto L
Xu Z
Garcia-Tercero L
Mateos-Sánchez C
Lozano JJ
Dotti I
Poisson J
Tanguy M
Salas A
Rautou PE
Bataller R
Sancho-Bru P
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv alcohol-related liver disease
alcohol-associated hepatitis
senescence
GDF15
topic alcohol-related liver disease
alcohol-associated hepatitis
senescence
GDF15
description Background & Aims: Cellular senescence is characterized by the loss of proliferative capacity, cell cycle arrest, and the acquisition of a proinflammatory senescence-associated secretory phenotype (SASP). Senescence is frequently present in advanced chronic liver diseases; however, the impact of hepatocellular senescence in alcohol-associated liver disease (ALD) progression and alcohol-associated hepatitis (AH) is poorly understood. Methods: Senescence was evaluated in transcriptomic data from patients at different ALD stages: advanced fibrosis (n = 10), cirrhosis (n = 10), and AH (n = 29). Plasma GDF15 levels were tested in patients with AH (n = 68), compensated cirrhosis (n = 15), heavy drinkers without liver disease (n = 15), and healthy controls (n = 10). Results were confirmed in an independent validation cohort. Results: Transcriptomic analysis revealed an increased expression of senescence-associated genes and an enrichment of SASP gene signatures in patients with cirrhosis and particularly with AH. The association of senescence with AH was confirmed by p21 staining and the expression of senescence markers (i.e. CDKN1A, CDKN2A, CDKN2B, IL6, and SERPINE1), which positively correlated with clinical severity scores. Among the SASP factors, GDF15 was expressed in the hepatocytes of patients with AH and was strongly associated with senescence markers. Circulating GDF15 levels were specifically increased in patients with AH and positively correlated with severity scores. Moreover, plasma GDF15 levels predicted the response to corticosteroids and 90-day mortality in two independent cohorts of patients with AH. Conclusions: These results suggest that AH is characterized by the presence of hepatocellular senescence and elevated circulating levels of SASP factors, particularly GDF15, which correlates with patients' poor outcomes. This suggests that senescence may be both a player in AH pathogenesis and a potential biomarker for AH.<br /> (c) 2025 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://incliva.portalinvestigacion.com/publicaciones/20285
url https://incliva.portalinvestigacion.com/publicaciones/20285
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv ELSEVIER
publisher.none.fl_str_mv ELSEVIER
dc.source.none.fl_str_mv JHEP Reports
ISSN: 25895559
reponame:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
instname:INCLIVA
instname_str INCLIVA
reponame_str r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
collection r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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