Therapeutic breakthroughs in acute-on-chronic liver failure: From conventional approaches to emerging targeted therapies

Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome characterized by acute decompensation of chronic liver disease, multisystem organ failure, and high short-term mortality. Current standard-of-care, including comprehensive medical management and non-biological artificial liver support, primarily focuses on symptomatic relief and bridging to transplantation. However, these traditional approaches are limited by donor shortages, high costs, and an inability to reverse the core pathological deterioration. This review aims to systematically analyze the pathophysiological mechanisms of ACLF and provide an in-depth evaluation of emerging targeted therapies that signal a paradigm shift from passive support to active functional regeneration. The article first delineates the evolving definitions and diagnostic criteria of ACLF, identifying systemic inflammation, immune paresis, and mitochondrial dysfunction as the central drivers of disease progression. Against this background, the review categorizes and critically assesses a wide array of novel therapeutic strategies. Key interventions discussed include: (1) stem cell therapies: the efficacy of mesenchymal stem cells (MSCs) and gene-modified MSCs in modulating immunity and promoting tissue repair; (2) advanced support systems: the evolution from mechanical filtration to bioartificial livers (BAL) and 3D-printed hepatic organoids; (3) immunomodulation and molecular targeting: novel biologic agents and targets such as recombinant alkaline phosphatase (RecAP), gasdermin D (GSDMD)-mediated pyroptosis inhibitors, mitochondrial fusion protein 2 (Mfn2), and thrombospondin-1 (THBS1); and (4) microbiome interventions: the role of fecal microbiota transplantation (FMT) in restoring the gut-liver axis. Additionally, the potential of traditional Chinese medicine (TCM) and network pharmacology is explored.While emerging therapies demonstrate significant potential to inhibit the ″cytokine storm″, restore metabolic homeostasis, and facilitate liver regeneration, challenges regarding safety protocols, standardization, and clinical translation remain. The authors propose that the future of ACLF treatment lies in precision medicine, facilitated by single-cell multi-omics analysis and artificial intelligence, to stratify patients for individualized regimens. Ultimately, the therapeutic landscape is transitioning from ″organ replacement″ to ″functional regeneration″ and ″immune restoration", offering a promising roadmap for achieving clinical cures and improving long-term survival in ACLF patients. <alternatives id="alt2"> </alternatives>