Acute-on-chronic liver failure and immune dysregulation: Systemic inflammation and immunoparesis paradox

Acute-on-chronic liver failure (ACLF) is a severe clinical syndrome characterized by abrupt hepatic decompensation and systemic inflammation in patients with underlying chronic liver disease, frequently progressing to multi-organ failure and high short-term mortality. Although ACLF is increasingly recognized as a distinct clinical entity, its pathogenesis remains incompletely understood, and diagnostic criteria vary across international guidelines. Central to ACLF is immune dysregulation, driven by systemic inflammation triggered by bacterial translocation, pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs), alongside immunoparesis resulting from sustained immune activation. This review synthesizes current preclinical and clinical evidence on ACLF's classification, underlying mechanisms, and the dynamic interplay between hepatic injury, immune dysfunction, and organ failure. In addition, we highlight emerging biomarkers and the therapeutic strategies aimed at improving diagnostic accuracy and patient outcomes.