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<p>The mechanisms driving the progression from acutely decompensated (AD) cirrhosis to acute-on-chronic liver failure (ACLF), a high mortality condition, remain poorly understood. In this study, we integrate multiomics and clinical data from 766 AD patients to construct multiscale, multifactorial response networks associated with two major outcomes: ACLF development and death. Among 291 features, 22 are linked to ACLF development and 16 to mortality. These features constitute a network connecting mitochondrial dysfunction with the accumulation of the lipid mediator 20-hydroxyeicosatetraenoic acid (20-HETE). In vitro validation of this network in human peripheral leukocytes shows that 20-HETE induces mitochondrial oxidative stress and impairs mitochondrial respiration via a GPR75-Akt signaling pathway. Network features also act as early predictors of AD outcomes, a finding validated in an independent cohort of 580 patients. Here, we show a strong link between dysregulated immunomodulatory lipid mediators and mitochondrial dysfunction driving ACLF development and mortality risk in advanced cirrhosis.</p>

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Blood multiomics reveal a dysregulated lipid mediator-mitochondrial network associated with the outcome of advanced cirrhosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月22日

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  • Cristina López-Vicario,
  • Ferran Aguilar,
  • Fleur Chapus,
  • Carlos de la Peña-Ramirez,
  • François Fenaille,
  • Florence Castelli,
  • Marta Duran-Güell,
  • Bryan J. Contreras,
  • Berta Romero-Grimaldo,
  • María Belén Sánchez-Rodríguez,
  • Laura Valls-Roca,
  • Glòria Garrabou,
  • Sara Palomino-Echeverria,
  • Estefania Huergo,
  • Cristina Sanchez-Garrido,
  • Wim Laleman,
  • David Gómez-Cabrero,
  • Alberto Queiroz Farias,
  • Sebastián Marciano,
  • Paolo Caraceni,
  • Jonel Trebicka,
  • Javier Fernández,
  • Christophe Junot,
  • Esther Titos,
  • Richard Moreau,
  • Vicente Arroyo,
  • Pierre-Emmanuel Rautou,
  • Joan Clària

摘要

The mechanisms driving the progression from acutely decompensated (AD) cirrhosis to acute-on-chronic liver failure (ACLF), a high mortality condition, remain poorly understood. In this study, we integrate multiomics and clinical data from 766 AD patients to construct multiscale, multifactorial response networks associated with two major outcomes: ACLF development and death. Among 291 features, 22 are linked to ACLF development and 16 to mortality. These features constitute a network connecting mitochondrial dysfunction with the accumulation of the lipid mediator 20-hydroxyeicosatetraenoic acid (20-HETE). In vitro validation of this network in human peripheral leukocytes shows that 20-HETE induces mitochondrial oxidative stress and impairs mitochondrial respiration via a GPR75-Akt signaling pathway. Network features also act as early predictors of AD outcomes, a finding validated in an independent cohort of 580 patients. Here, we show a strong link between dysregulated immunomodulatory lipid mediators and mitochondrial dysfunction driving ACLF development and mortality risk in advanced cirrhosis.