{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T12:58:22Z","timestamp":1791377902037,"version":"4.3.2"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"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 encephalopathy (SAE) represents the most prevalent neurological complication arising from sepsis, affecting approximately 70% of patients with sepsis and associated with mortality rates reaching up to 70%. Survivors frequently experience persistent cognitive deficits; however, the field currently lacks specific diagnostic biomarkers and targeted therapeutic interventions, with diagnosis primarily established through exclusion criteria. This review critically examines multi-omic investigations of SAE, evaluating whether convergent evidence across genomic, transcriptomic, proteomic, and metabolomic domains elucidates shared pathophysiological mechanisms and identifying prevailing translational challenges. The synthesis of evidence is structured around three interrelated thematic domains. First, multi-omic analyses have elucidated the initial triggers of neuroinflammation: genomic studies implicate Piezo1-mediated oligodendrocyte ferroptosis and adenosine-to-inosine (A-to-I) RNA editing, while proteomic data corroborate activation of the reactive oxygen species (ROS)\/thioredoxin-interacting protein (TXNIP)\/NLRP3 inflammasome axis, collectively indicating that peripheral inflammatory cues converge upon central innate immune pathways. Second, transcriptomic and proteomic findings converge on microglial polarization as a pivotal mediator in SAE progression: single-cell sequencing reveals C1q-dependent synaptic pruning, S100A9 protein expression promotes pro-inflammatory microglial polarization, and metabolomic profiles demonstrate that cyclophilin D (CypD)-regulated redox imbalances modulate the magnitude of glial inflammatory responses. Third, integrative analyses delineate neuronal injury pathways: the NAT10 (N-acetyltransferase 10)\/GABA(B) receptor 1 axis is implicated in inhibitory synaptic dysfunction through coordinated transcriptomic and proteomic alterations, while elevated levels of 4-hydroxyphenylacetic acid correlate with impaired consciousness, suggesting its potential utility as a prognostic biomarker. Across these domains\u2014initiation, mediation, and injury\u2014multi-omic integration further extends the conceptual framework to encompass systemic regulation via the microbiota\u2013gut\u2013brain axis. Notwithstanding these advances, extant evidence is limited by predominantly cross-sectional study designs, reliance on single-animal models, and a paucity of rigorous clinical validation. To address these limitations, we propose a three-tiered cascade model\u2014comprising Inflammation Initiation, Glial Mediation, and Neuronal Injury\u2014that synthesizes current findings into a coherent, testable framework. Furthermore, we delineate a methodological roadmap emphasizing longitudinal sampling, multi-center validation, causal inference methodologies, and artificial intelligence-driven data integration. This review endeavors not only to consolidate existing knowledge but also to establish an actionable translational paradigm aimed at advancing SAE research from descriptive characterization toward precision diagnostics and mechanism-based therapeutic strategies.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1941590","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T11:59:16Z","timestamp":1791374356000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-omics advances in sepsis-associated encephalopathy: from pathogenesis to clinical translation"],"prefix":"10.3389","volume":"17","author":[{"given":"Linlin","family":"Gao","sequence":"first","affiliation":[{"name":"Department of General Practice, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuehua","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of General Practice, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.0287","article-title":"The third international consensus definitions for sepsis and septic shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"B2","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1186\/s13643-024-02583-4","article-title":"Clinical value of serum neuron-specific enolase in sepsis-associated encephalopathy: a systematic review and meta-analysis","volume":"13","author":"Zhi","year":"2024","journal-title":"Systematic 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