{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T17:24:37Z","timestamp":1793381077273,"version":"4.5.0"},"reference-count":116,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Sepsis-associated liver injury (SALI) is a critical determinant of sepsis prognosis, characterized by extensive hepatocellular death and dysregulated immune responses. Emerging evidence highlights the pivotal role of regulated cell death (RCD) \u2014 including apoptosis, necroptosis, pyroptosis, and ferroptosis \u2014 in driving hepatic dysfunction and systemic inflammation. These cell death modalities, once considered distinct, are now recognized as components of an interconnected network that integrates inflammatory, metabolic, and oxidative signals within the liver\u2019s unique immunometabolic microenvironment. This review systematically summarizes the molecular mechanisms of major RCD pathways implicated in SALI, and elucidates their crosstalk and convergence through shared mediators such as caspase-8, the NLRP3 inflammasome, lipid peroxidation, and liver-specific metabolic regulators including bile acid signaling. We further discuss key signaling cascades including PI3K\/Akt, Nrf2, and NF-\u03baB that orchestrate RCD execution and inflammatory amplification in SALI. By integrating mechanistic insights with emerging translational perspectives, this review highlights RCD as a unifying framework for understanding liver injury and identifying therapeutic entry points to restore hepatic and systemic homeostasis during sepsis.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1740461","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T06:50:45Z","timestamp":1770792645000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Regulated cell death in sepsis-associated liver injury: molecular mechanisms and therapeutic implications"],"prefix":"10.3389","volume":"17","author":[{"given":"Kun","family":"Zou","sequence":"first","affiliation":[{"name":"Department of General Surgery, The Second Hospital and Clinical Medical School, Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The Second Hospital and Clinical Medical School, Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The Second Hospital and Clinical Medical School, Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongqiang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, The Second Hospital and Clinical Medical School, Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyuan","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, The Second Hospital and Clinical Medical School, Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junqiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, The Second Hospital and Clinical Medical School, Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.36","article-title":"The immunopathology of sepsis and potential therapeutic targets","volume":"17","author":"van der Poll","year":"2017","journal-title":"Nat Rev Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.2147\/IDR.S489196","article-title":"Establishment and validation of a risk prediction model for sepsis-associated liver injury in ICU patients: A retrospective cohort study","volume":"18","author":"Li","year":"2025","journal-title":"Infect Drug Resist"},{"key":"B4","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1186\/s13054-020-03327-1","article-title":"Gut-liver crosstalk in sepsis-induced liver injury","volume":"24","author":"Sun","year":"2020","journal-title":"Crit Care"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.10.012","article-title":"The immunology of sepsis","volume":"54","author":"van der Poll","year":"2021","journal-title":"Immunity."},{"key":"B6","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1038\/nrgastro.2016.168","article-title":"Liver - 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