{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T10:08:28Z","timestamp":1784542108210,"version":"3.55.0"},"reference-count":119,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T00:00:00Z","timestamp":1784419200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Acute-on-chronic liver failure (ACLF) is a rapidly progressing and highly lethal clinical syndrome characterized by multiorgan failure, driven primarily by a severe systemic inflammatory response. The pathophysiological cascade, triggered by a \u201ccytokine storm,\u201d subsequently evolves into profound immune paralysis. This phenomenon is driven by the dysfunction of monocytes, neutrophils, and other immune cells, compounded by their impaired cellular energetics resulting from a metabolic shift toward less efficient energy-yielding mechanisms, mainly aerobic glycolysis, with the pentose phosphate pathway contributing NADPH and biosynthetic precursors rather than ATP. This process is further exacerbated by disruptions within the gut\u2013liver axis, wherein severe dysbiosis and impaired intestinal barrier integrity promote pathogen translocation. Beyond the gut, the liver\u2013spleen axis constitutes a second amplification loop: the congested and immunologically remodeled spleen is proposed to sustain portal hypertension, to contribute to the circulating cytokine pool and to relay profibrogenic signals back to the liver. Coupled with generalized endothelial dysfunction, this is thought to contribute to the failure of peripheral organs. This cascade is presented as a synthesizing model of partially overlapping mechanistic hypotheses and heterogeneous evidence\u2014much of it derived from studies in cirrhosis or animal models and still requiring deeper, ACLF-specific investigation rather than a fully established, strictly linear sequence. To date, no specific targeted therapies are available, and liver transplantation remains the sole intervention capable of substantially improving patient prognosis. Experimental immunomodulatory approaches including granulocyte colony-stimulating factor (G-CSF), intravenous albumin supplementation, therapeutic plasma exchange, mesenchymal stem cell therapy, and anti-cytokine agents represent promising therapeutic avenues. Nevertheless, appropriately tailoring these interventions to the evolving pathophysiological phases of the disease remains a significant clinical challenge, underscoring the critical need for developing precision therapies targeted at specific molecular pathways.<\/jats:p>","DOI":"10.3390\/ijms27146414","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T09:32:54Z","timestamp":1784539974000},"page":"6414","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Acute-on-Chronic Liver Failure: An Eroded Cliff Hit by a Storm\u2014A Narrative Review"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7866-4830","authenticated-orcid":false,"given":"Kinga","family":"Knop-Chody\u0142a","sequence":"first","affiliation":[{"name":"Doctoral School of the Medical University of Lublin, Medical University of Lublin, Witolda Chod\u017aki 7, 20-093 Lublin, Poland"},{"name":"Department of Gastroenterology and Hepatology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7198-4428","authenticated-orcid":false,"given":"Beata","family":"Kasztelan-Szczerbinska","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Halina","family":"Cicho\u017c-Lach","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1053\/j.gastro.2013.02.042","article-title":"Acute-on-Chronic Liver Failure Is a Distinct Syndrome That Develops in Patients with Acute Decompensation of Cirrhosis","volume":"144","author":"Moreau","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12072-024-10773-4","article-title":"Acute-on-Chronic Liver Failure (ACLF): The \u2018Kyoto Consensus\u2019\u2014Steps from Asia","volume":"19","author":"Choudhury","year":"2025","journal-title":"Hepatol. 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