{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T16:44:51Z","timestamp":1791996291299,"version":"4.4.0"},"reference-count":116,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002855","name":"Ministry of Science and Technology of the People\u2019s Republic of China","doi-asserted-by":"publisher","award":["STI2030-Major Projects2021ZD0201900"],"award-info":[{"award-number":["STI2030-Major Projects2021ZD0201900"]}],"id":[{"id":"10.13039\/501100002855","id-type":"DOI","asserted-by":"publisher"}]},{"award":["STI2030-Major Projects2021ZD0201900"],"award-info":[{"award-number":["STI2030-Major Projects2021ZD0201900"]}],"id":[{"id":"https:\/\/ror.org\/027s68j25","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Sepsis-associated encephalopathy (SAE) is a frequent neurological complication of sepsis, driven by six interconnected pathophysiological components: (1) systemic inflammation-triggered neuroinflammatory cascades, initiated by systemic recognition of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and propagated by pro-inflammatory mediators; (2) central nervous system (CNS) immune cell-mediated neuroinflammation, wherein microglia, regulatory T cells, and neutrophils dynamically regulate inflammatory progression; (3) blood\u2013brain barrier (BBB) disruption, progressing from functional disturbance to structural damage via tight junction degradation and immune infiltration; (4) multimodal programmed cell death, encompassing autophagy, apoptosis, pyroptosis, and ferroptosis driven by mitochondrial dysfunction; (5) neurotransmitter network imbalance, manifesting as cholinergic deficiency and glutamate excitotoxicity; and (6) gut\u2013brain axis dysregulation, characterized by reduced microbiota-derived metabolites such as butyrate and indolepropionic acid. These components are organized along a core pathological axis comprising four sequential stages: neuroinflammatory storm (encompassing components 1 and 2) \u2192 BBB disruption and microcirculatory disturbances (component 3) \u2192 multimodal programmed cell death (component 4) \u2192 neurotransmitter imbalance (component 5), with the gut\u2013brain axis (component 6) functioning as a bidirectional regulatory node that intersects and modulates all four stages. Mitochondrial dysfunction serves as the central converging node linking these pathological axes. Targeted interventions against neuroinflammation, immune cell modulation, BBB restoration, inhibition of aberrant cell death, neurotransmitter homeostasis, and gut microbiota remodeling hold therapeutic promise. Elucidating the crosstalk among these pathways will accelerate the clinical translation of precision therapies for SAE.<\/jats:p>","DOI":"10.3390\/ijms27125390","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:49:01Z","timestamp":1781570941000},"page":"5390","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Research Advances in the Pathogenesis of Sepsis-Associated Encephalopathy"],"prefix":"10.3390","volume":"27","author":[{"given":"Haowen","family":"Tan","sequence":"first","affiliation":[{"name":"Department of Emergency Medicine, West China Hospital, Sichuan University, Chengdu 610041, China"},{"name":"West China School of Clinical Medicine, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Science and Technology, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhendong","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/nrneurol.2012.183","article-title":"Sepsis-associated encephalopathy","volume":"8","author":"Gofton","year":"2012","journal-title":"Nat. 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