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 impac...
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2025-09-01
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| author | Teresa Rubio-Tomás David Martí-Aguado Delia Blaya Silvia Ariño Beatriz Aguilar-Bravo Raquel A. Martínez García de la Torre Marc Miravet-Marti Raquel Ferrer-Lorente Laura Zanatto Zengqing Xu Laura Garcia-Tercero Carlos Mateos-Sánchez Juan José Lozano Isabella Dotti Johanne Poisson Marion Tanguy Azucena Salas Pierre-Emmanuel Rautou Ramon Bataller Pau Sancho-Bru |
| author_facet | Teresa Rubio-Tomás David Martí-Aguado Delia Blaya Silvia Ariño Beatriz Aguilar-Bravo Raquel A. Martínez García de la Torre Marc Miravet-Marti Raquel Ferrer-Lorente Laura Zanatto Zengqing Xu Laura Garcia-Tercero Carlos Mateos-Sánchez Juan José Lozano Isabella Dotti Johanne Poisson Marion Tanguy Azucena Salas Pierre-Emmanuel Rautou Ramon Bataller Pau Sancho-Bru |
| author_sort | Teresa Rubio-Tomás |
| collection | DOAJ |
| 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. Impact and implications: The pathogenesis of alcohol-associated liver disease (ALD) and hepatitis (AH) remains to be fully elucidated, and there is a need for biomarkers that can effectively monitor disease progression and assess patient response to therapy. In this study, we show the association of AH with hepatocellular senescence and the hepatic expression of senescence-associated secretory phenotype (SASP) factors, which correlate with poor patient outcome. Furthermore, we provide evidence that SASP factors such as GDF15 may be potential plasma biomarkers for AH. The findings of this study lay the groundwork for future research into the role of senescence in the pathogenesis of AH, as well as into the potential use of senescence and SASP-related molecules as biomarkers for AH. |
| format | Article |
| id | doaj-art-1fbe79e4cd47482fa35a238b052f5977 |
| institution | Kabale University |
| issn | 2589-5559 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
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| series | JHEP Reports |
| spelling | doaj-art-1fbe79e4cd47482fa35a238b052f59772025-08-20T03:58:00ZengElsevierJHEP Reports2589-55592025-09-017910147810.1016/j.jhepr.2025.101478GDF15 is associated with hepatocellular senescence and correlates with mortality in patients with alcohol-associated hepatitisTeresa Rubio-Tomás0David Martí-Aguado1Delia Blaya2Silvia Ariño3Beatriz Aguilar-Bravo4Raquel A. Martínez García de la Torre5Marc Miravet-Marti6Raquel Ferrer-Lorente7Laura Zanatto8Zengqing Xu9Laura Garcia-Tercero10Carlos Mateos-Sánchez11Juan José Lozano12Isabella Dotti13Johanne Poisson14Marion Tanguy15Azucena Salas16Pierre-Emmanuel Rautou17Ramon Bataller18Pau Sancho-Bru19Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, SpainDigestive Disease Department, Clinic University Hospital, INCLIVA Health Research Institute, Valencia, SpainInstitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, SpainInstitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, SpainInstitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, SpainInstitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, SpainInstitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, SpainInstitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, SpainInstitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, SpainInstitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Faculty of Medicine, University of Barcelona, Barcelona, SpainInstitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, SpainInstitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, SpainInstitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red, Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, SpainInstitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red, Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, SpainUniversité Paris-Cité, Inserm, Centre de recherche sur l'inflammation, UMR 1149, Paris, France; AP-HP, Paris Cancer Institute CARPEM, European Hospital Georges Pompidou, Department of geriatrics, Paris, FranceUniversité Paris-Cité, Inserm, Centre de recherche sur l'inflammation, UMR 1149, Paris, FranceInstitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red, Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, SpainUniversité Paris-Cité, Inserm, Centre de recherche sur l'inflammation, UMR 1149, Paris, France; AP-HP, Hôpital Beaujon, Service d'Hépatologie, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Clichy, FranceCentro de Investigación Biomédica en Red, Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Liver Unit, Hospital Clínic, Barcelona, SpainInstitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Faculty of Medicine, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red, Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Corresponding author. Address: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), C/ Rosselló, 149-153, 08036 Barcelona, Spain.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. Impact and implications: The pathogenesis of alcohol-associated liver disease (ALD) and hepatitis (AH) remains to be fully elucidated, and there is a need for biomarkers that can effectively monitor disease progression and assess patient response to therapy. In this study, we show the association of AH with hepatocellular senescence and the hepatic expression of senescence-associated secretory phenotype (SASP) factors, which correlate with poor patient outcome. Furthermore, we provide evidence that SASP factors such as GDF15 may be potential plasma biomarkers for AH. The findings of this study lay the groundwork for future research into the role of senescence in the pathogenesis of AH, as well as into the potential use of senescence and SASP-related molecules as biomarkers for AH.http://www.sciencedirect.com/science/article/pii/S2589555925001569alcohol-related liver diseasealcohol-associated hepatitissenescenceGDF15 |
| spellingShingle | Teresa Rubio-Tomás David Martí-Aguado Delia Blaya Silvia Ariño Beatriz Aguilar-Bravo Raquel A. Martínez García de la Torre Marc Miravet-Marti Raquel Ferrer-Lorente Laura Zanatto Zengqing Xu Laura Garcia-Tercero Carlos Mateos-Sánchez Juan José Lozano Isabella Dotti Johanne Poisson Marion Tanguy Azucena Salas Pierre-Emmanuel Rautou Ramon Bataller Pau Sancho-Bru GDF15 is associated with hepatocellular senescence and correlates with mortality in patients with alcohol-associated hepatitis JHEP Reports alcohol-related liver disease alcohol-associated hepatitis senescence GDF15 |
| title | 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_short | 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 |
| topic | alcohol-related liver disease alcohol-associated hepatitis senescence GDF15 |
| url | http://www.sciencedirect.com/science/article/pii/S2589555925001569 |
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