Rubio-Tomás Teresa, Martí-Aguado David, Blaya Delia, Ariño Silvia, Aguilar-Bravo Beatriz, Martínez García de la Torre Raquel A, Miravet-Marti Marc, Ferrer-Lorente Raquel, Zanatto Laura, Xu Zengqing, Garcia-Tercero Laura, Mateos-Sánchez Carlos, Lozano Juan José, Dotti Isabella, Poisson Johanne, Tanguy Marion, Salas Azucena, Rautou Pierre-Emmanuel, Bataller Ramon, Sancho-Bru Pau
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Digestive Disease Department, Clinic University Hospital, INCLIVA Health Research Institute, Valencia, Spain.
JHEP Rep. 2025 Jun 10;7(9):101478. doi: 10.1016/j.jhepr.2025.101478. eCollection 2025 Sep.
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.
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.
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 (. 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.
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.
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.
细胞衰老的特征是增殖能力丧失、细胞周期停滞以及获得促炎的衰老相关分泌表型（SASP）。衰老在晚期慢性肝病中很常见；然而，肝细胞衰老在酒精性肝病（ALD）进展和酒精性肝炎（AH）中的影响尚不清楚。
在不同ALD阶段患者的转录组数据中评估衰老情况：重度纤维化（n = 10）、肝硬化（n = 10）和AH（n = 29）。检测了AH患者（n = 68）、代偿期肝硬化患者（n = 15）、无肝病的重度饮酒者（n = 15）和健康对照者（n = 10）的血浆GDF15水平。在一个独立的验证队列中证实了结果。
转录组分析显示，肝硬化患者尤其是AH患者中衰老相关基因的表达增加，且SASP基因特征富集。通过p21染色以及衰老标志物（CDKN1A、CDKN2A、CDKN2B、IL6和SERPINE1）的表达证实了衰老与AH的关联，这些标志物与临床严重程度评分呈正相关。在SASP因子中，GDF15在AH患者的肝细胞中表达，并与衰老标志物密切相关。AH患者的循环GDF15水平特异性升高，且与严重程度评分呈正相关。此外，血浆GDF15水平可预测两个独立AH患者队列对皮质类固醇的反应和90天死亡率。
这些结果表明，AH的特征是肝细胞衰老以及SASP因子循环水平升高，尤其是GDF15，这与患者的不良预后相关。这表明衰老可能既是AH发病机制中的一个因素，也是AH的一个潜在生物标志物。
酒精性肝病（ALD）和肝炎（AH）的发病机制仍有待充分阐明，需要能够有效监测疾病进展并评估患者对治疗反应的生物标志物。在本研究中，我们展示了AH与肝细胞衰老以及衰老相关分泌表型（SASP）因子的肝脏表达之间的关联，这与患者的不良预后相关。此外，我们提供证据表明，诸如GDF15等SASP因子可能是AH的潜在血浆生物标志物。本研究结果为未来研究衰老在AH发病机制中的作用以及衰老和SASP相关分子作为AH生物标志物的潜在用途奠定了基础。
