Neuroepigenetic regulation by long non-coding RNAs in sepsis-associated encephalopathy: cell-type programs and translational biomarkers.

Sepsis-associated encephalopathy (SAE) is a frequent complication of sepsis in which systemic inflammation precipitates central nervous system (CNS) dysfunction without overt CNS infection. Long noncoding RNAs (lncRNAs) are emerging as upstream regulators of cell-type–specific inflammatory and stress programs in brain-resident immune and barrier-associated cells, with potential implications for blood–brain barrier (BBB) integrity and synaptic homeostasis. Across clinical cohorts and experimental models, NEAT1, MALAT1, MEG3, taurine upregulated gene 1 (TUG1) and TapSAKI have been linked to nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling, oxidative stress and ferroptosis-related responses. Several candidates act within competing endogenous RNA (ceRNA) networks that tune post-transcriptional inflammatory amplitude and survival decisions. Translationally, blood-based and cerebrospinal fluid (CSF) lncRNAs, including extracellular vesicle (EV)–associated species, correlate with illness severity and organ dysfunction, supporting evaluation as adjunct biomarkers contingent on rigorous pre-analytics and transparent adjustment for disease severity. RNA-targeting modalities such as antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) are plausible, but sepsis imposes stringent constraints on timing, delivery, biodistribution, and immune safety, and requires clear evidence of exposure and on-target engagement. We outline practical priorities—assay standardization, human-anchored causal validation, and pharmacokinetic/tissue-distribution benchmarks—and emphasize that direct evidence linking lncRNA modulation to restoration of BBB or vascular phenotypes in sepsis remains limited.