The Essential Role of Architectural Noncoding RNA Neat1 in Cold-Induced Beige Adipocyte Differentiation in Mice.

Neat1 is an architectural RNA that provides the structural basis for nuclear bodies known as paraspeckles. Although the assembly processes by which Neat1 organizes paraspeckle components are well-documented, the physiological functions of Neat1 remain less defined. This is partly because Neat1 knockout (KO) mice, lacking paraspeckles, do not exhibit overt phenotypes under normal laboratory conditions. During our search for conditions that elicit clear phenotypes in Neat1 KO mice, we discovered that the differentiation of beige adipocytes-inducible thermogenic cells that emerge upon cold exposure-is severely impaired in these mutant mice. Neat1_2, the architectural isoform of Neat1, is transiently upregulated during the early stages of beige adipocyte differentiation, coinciding with increased paraspeckle formation. Genes with altered expression during beige adipocyte differentiation typically cluster at specific chromosomal locations, some of which move closer to paraspeckles upon cold exposure. These observations suggest that paraspeckles might coordinate the regulation of these gene clusters by controlling the activity of certain transcriptional condensates that co-regulate multiple genes. We propose that our findings highlight a potential role for Neat1 and paraspeckles in modulating chromosomal organization and gene expression, potentially crucial processes for the differentiation of beige adipocytes.

The early macrophage response to pathogens requires dynamic regulation of the nuclear paraspeckle.

To ensure a robust immune response to pathogens without risking immunopathology, the kinetics and amplitude of inflammatory gene expression in macrophages need to be exquisitely well controlled. There is a growing appreciation for stress-responsive membraneless organelles (MLOs) regulating various steps of eukaryotic gene expression in response to extrinsic cues. Here, we implicate the nuclear paraspeckle, a highly ordered biomolecular condensate that nucleates on the Neat1 lncRNA, in tuning innate immune gene expression in murine macrophages. In response to a variety of innate agonists, macrophage paraspeckles rapidly aggregate (0.5 h poststimulation) and disaggregate (2 h poststimulation). Paraspeckle maintenance and aggregation require active transcription and MAPK signaling, whereas paraspeckle disaggregation requires degradation of Neat1 via the nuclear RNA exosome. In response to lipopolysaccharide treatment, Neat1 KO macrophages fail to properly express a large cohort of proinflammatory cytokines, chemokines, and antimicrobial mediators. Consequently, Neat1 KO macrophages cannot control replication of Salmonella enterica serovar Typhimurium or vesicular stomatitis virus. These findings highlight a prominent role for MLOs in orchestrating the macrophage response to pathogens and support a model whereby dynamic assembly and disassembly of paraspeckles reorganizes the nuclear landscape to enable inflammatory gene expression following innate stimuli.

Gastric inflammatory myofibroblastic tumor presented with severe anemia and inflammation: a case report.

BACKGROUND: Inflammatory myofibroblastic tumor (IMT) is a rare stromal tumor, often found in children and young adults, and most commonly occurs in the lungs. Surgical resection is considered the standard treatment for localized IMT, although only limited data exist. Gastric IMT in adults is extremely rare, and there are no established guidelines for its treatment. CASE PRESENTATION: A 69-year-old male presented with persistent fatigue and weakness. Laboratory examination revealed severe anemia and inflammation. Upper gastrointestinal endoscopy at admission revealed a 40-mm type I softish tumor in the lesser curvature of the gastric body, without apparent hemorrhage. Repeated biopsies, including partial resection with snare, failed to give a definitive diagnosis. Computed tomography (CT) revealed a massive lesion at the gastric body, protruding into the gastric lumen, which was consistent with the gastric tumor. After admission, the patient developed anemia refractory to frequent blood transfusions despite the absence of apparent gastrointestinal bleeding. In addition, the patient had recurrent fevers of 38 °C or higher, and persistent high inflammatory levels. Fluorodeoxyglucose-positron emission tomography (FDG-PET) CT 1 month after the first visit exhibited an increased FDG uptake in the gastric tumor. In addition, this CT scan revealed a rapid increase in tumor size to 75 mm. It was suspected that the undiagnosed gastric tumor caused these serious clinical symptoms, and he underwent distal gastrectomy and cholecystectomy. The gross image of the tumor showed an 80-mm cauliflower-like shape with a gelatinous texture. The histopathological diagnosis was IMT. The postoperative course was uneventful, and the patient's symptoms subsided drastically, improving both anemia and systemic inflammation. The patient has shown no recurrence or relapse of the symptoms over one and a half years. CONCLUSIONS: In this case, the tumor resection finally enabled the diagnosis of IMT and resolved the clinical symptoms. Despite its predominantly benign morphological nature, some cases of IMT present clinically adverse courses. Surgical treatment may lead to its final diagnosis and improvement of clinical symptoms.

4.5SH RNA counteracts deleterious exonization of SINE B1 in mice.

4.5SH RNA is a highly abundant, small rodent-specific noncoding RNA that localizes to nuclear speckles enriched in pre-mRNA-splicing regulators. To investigate the physiological functions of 4.5SH RNA, we have created mutant mice that lack the expression of 4.5SH RNA. The mutant mice exhibited embryonic lethality, suggesting that 4.5SH RNA is an essential species-specific noncoding RNA in mice. RNA-sequencing analyses revealed that 4.5SH RNA protects the transcriptome from abnormal exonizations of the antisense insertions of the retrotransposon SINE B1 (asB1), which would otherwise introduce deleterious premature stop codons or frameshift mutations. Mechanistically, 4.5SH RNA base pairs with complementary asB1-containing exons via the target recognition region and recruits effector proteins including Hnrnpm via its 5' stem loop region. The modular organization of 4.5SH RNA allows us to engineer a programmable splicing regulator to induce the skipping of target exons of interest. Our results also suggest the general existence of splicing regulatory noncoding RNAs.

Nascent ribosomal RNA act as surfactant that suppresses growth of fibrillar centers in nucleolus.

Liquid-liquid phase separation (LLPS) has been thought to be the biophysical principle governing the assembly of the multiphase structures of nucleoli, the site of ribosomal biogenesis. Condensates assembled through LLPS increase their sizes to minimize the surface energy as far as their components are available. However, multiple microphases, fibrillar centers (FCs), dispersed in a nucleolus are stable and their sizes do not grow unless the transcription of pre-ribosomal RNA (pre-rRNA) is inhibited. To understand the mechanism of the suppression of the FC growth, we here construct a minimal theoretical model by taking into account nascent pre-rRNAs tethered to FC surfaces by RNA polymerase I. The prediction of this theory was supported by our experiments that quantitatively measure the dependence of the size of FCs on the transcription level. This work sheds light on the role of nascent RNAs in controlling the size of nuclear bodies.

Shell protein composition specified by the lncRNA NEAT1 domains dictates the formation of paraspeckles as distinct membraneless organelles.

Many membraneless organelles (MLOs) formed through phase separation play crucial roles in various cellular processes. Although these MLOs co-exist in cells, how they maintain their independence without coalescence or engulfment remains largely unknown. Here, we investigated the molecular mechanism by which paraspeckles with core-shell architecture scaffolded by NEAT1_2 long noncoding RNAs exist as distinct MLOs. We identified NEAT1 deletion mutants that assemble paraspeckles that are incorporated into nuclear speckles. Several paraspeckle proteins, including SFPQ, HNRNPF and BRG1, prevent this incorporation and thus contribute to the segregation of paraspeckles from nuclear speckles. Shell localization of these proteins in the paraspeckles, which is determined by NEAT1_2 long noncoding RNA domains, is required for this segregation process. Conversely, U2-related spliceosomal proteins are involved in internalizing the paraspeckles into nuclear speckles. This study shows that the paraspeckle shell composition dictates the independence of MLOs in the nucleus, providing insights into the importance of the shell in defining features and functions of MLOs.

Management of Patients Receiving Antiplatelet Therapy During Gastroenterological Surgery: A Multicenter Prospective Cohort Study (GSATT).

OBJECTIVE: This study aimed to evaluate the effect of continuing preoperative aspirin monotherapy on surgical outcomes in patients receiving antiplatelet therapy (APT). SUMMARY BACKGROUND DATA: The effectiveness of continuing preoperative aspirin monotherapy in patients undergoing APT in preventing thromboembolic consequences is mostly unknown. METHODS: This prospective multicenter cohort study on the Safety and Feasibility of Gastroenterological Surgery in Patients Undergoing Antithrombotic Therapy (GSATT study) conducted at 14 clinical centers enrolled and screened patients between October 2019 and December 2021. The participants (n=1,170) were assigned to the continued APT group, discontinued APT group, or non-APT group, and the surgical outcomes of each group were compared. Propensity score matching was performed between the continued and discontinued APT groups to investigate the effect of continuing preoperative aspirin therapy on thromboembolic complications. RESULTS: The rate of thromboembolic complications in the continued APT group was substantially lower than that in the non-APT or discontinued APT groups (0.5% vs. 2.6% vs. 2.9%; P=0.027). Multivariate investigation of the entire cohort revealed that discontinuation of APT (P<0.001) and chronic anticoagulant use (P<0.001) were independent risk factors for postoperative thromboembolism. The post-matching evaluation demonstrated that the rates of thromboembolic complications were significantly different between the continued and discontinued APT groups (0.6% vs. 3.3%; P=0.012). CONCLUSIONS: APT discontinuation following elective gastroenterological surgery increases the risk of thromboembolic consequences, whereas continuing preoperative aspirin greatly reduces this risk. The continuation of preoperative aspirin therapy in APT-received patients is considered one of the best alternatives for preventing thromboembolism during elective gastroenterological surgery.

Functional domains of nuclear long noncoding RNAs: Insights into gene regulation and intracellular architecture.

Recent functional research on long noncoding RNAs (lncRNAs) has revealed their significant regulatory roles in gene expression and intracellular architecture. Well-characterized examples of such lncRNAs include Xist and NEAT1_2, which play critical roles in heterochromatin formation of inactive X-chromosomes and paraspeckle assembly, in mammalian cells. Both lncRNAs possess modular domain structures with multiple functionally distinct domains that serve as platforms for specific RNA-binding proteins (RBPs), which dictate the function of each lncRNA. Some of these RBPs bind characteristic RNA structures, which can be targeted by small chemical compounds that modulate lncRNA function by perturbing the interaction of RBPs with the RNA structures. Therefore, RNA structures hidden in lncRNAs represent a novel and potent type of therapeutic target.

Satellite RNAs: emerging players in subnuclear architecture and gene regulation.

Satellite DNA is characterized by long, tandemly repeated sequences mainly found in centromeres and pericentromeric chromosomal regions. The recent advent of telomere-to-telomere sequencing data revealed the complete sequences of satellite regions, including centromeric α-satellites and pericentromeric HSat1-3, which together comprise ~ 5.7% of the human genome. Despite possessing constitutive heterochromatin features, these regions are transcribed to produce long noncoding RNAs with highly repetitive sequences that associate with specific sets of proteins to play various regulatory roles. In certain stress or pathological conditions, satellite RNAs are induced to assemble mesoscopic membraneless organelles. Specifically, under heat stress, nuclear stress bodies (nSBs) are scaffolded by HSat3 lncRNAs, which sequester hundreds of RNA-binding proteins. Upon removal of the stressor, nSBs recruit additional regulatory proteins, including protein kinases and RNA methylases, which modify the previously sequestered nSB components. The sequential recruitment of substrates and enzymes enables nSBs to efficiently regulate the splicing of hundreds of pre-mRNAs under limited temperature conditions. This review discusses the structural features and regulatory roles of satellite RNAs in intracellular architecture and gene regulation.

Landscape of semi-extractable RNAs across five human cell lines.

Phase-separated membraneless organelles often contain RNAs that exhibit unusual semi-extractability using the conventional RNA extraction method, and can be efficiently retrieved by needle shearing or heating during RNA extraction. Semi-extractable RNAs are promising resources for understanding RNA-centric phase separation. However, limited assessments have been performed to systematically identify and characterize semi-extractable RNAs. In this study, 1074 semi-extractable RNAs, including ASAP1, DANT2, EXT1, FTX, IGF1R, LIMS1, NEAT1, PHF21A, PVT1, SCMH1, STRG.3024.1, TBL1X, TCF7L2, TVP23C-CDRT4, UBE2E2, ZCCHC7, ZFAND3 and ZSWIM6, which exhibited consistent semi-extractability were identified across five human cell lines. By integrating publicly available datasets, we found that semi-extractable RNAs tend to be distributed in the nuclear compartments but are dissociated from the chromatin. Long and repeat-containing semi-extractable RNAs act as hubs to provide global RNA-RNA interactions. Semi-extractable RNAs were divided into four groups based on their k-mer content. The NEAT1 group preferred to interact with paraspeckle proteins, such as FUS and NONO, implying that RNAs in this group are potential candidates of architectural RNAs that constitute nuclear bodies.

Nondomain biopolymers: Flexible molecular strategies to acquire biological functions.

A long-standing assumption in molecular biology posits that the conservation of protein and nucleic acid sequences emphasizes the functional significance of biomolecules. These conserved sequences fold into distinct secondary and tertiary structures, enable highly specific molecular interactions, and regulate complex yet organized molecular processes within living cells. However, recent evidence suggests that biomolecules can also function through primary sequence regions that lack conservation across species or gene families. These regions typically do not form rigid structures, and their inherent flexibility is critical for their functional roles. This review examines the emerging roles and molecular mechanisms of "nondomain biomolecules," whose functions are not easily predicted due to the absence of conserved functional domains. We propose the hypothesis that both domain- and nondomain-type molecules work together to enable flexible and efficient molecular processes within the highly crowded intracellular environment.

Long non-coding RNAs: definitions, functions, challenges and recommendations.

Genes specifying long non-coding RNAs (lncRNAs) occupy a large fraction of the genomes of complex organisms. The term 'lncRNAs' encompasses RNA polymerase I (Pol I), Pol II and Pol III transcribed RNAs, and RNAs from processed introns. The various functions of lncRNAs and their many isoforms and interleaved relationships with other genes make lncRNA classification and annotation difficult. Most lncRNAs evolve more rapidly than protein-coding sequences, are cell type specific and regulate many aspects of cell differentiation and development and other physiological processes. Many lncRNAs associate with chromatin-modifying complexes, are transcribed from enhancers and nucleate phase separation of nuclear condensates and domains, indicating an intimate link between lncRNA expression and the spatial control of gene expression during development. lncRNAs also have important roles in the cytoplasm and beyond, including in the regulation of translation, metabolism and signalling. lncRNAs often have a modular structure and are rich in repeats, which are increasingly being shown to be relevant to their function. In this Consensus Statement, we address the definition and nomenclature of lncRNAs and their conservation, expression, phenotypic visibility, structure and functions. We also discuss research challenges and provide recommendations to advance the understanding of the roles of lncRNAs in development, cell biology and disease.

A guide to membraneless organelles and their various roles in gene regulation.

Membraneless organelles (MLOs) are detected in cells as dots of mesoscopic size. By undergoing phase separation into a liquid-like or gel-like phase, MLOs contribute to intracellular compartmentalization of specific biological functions. In eukaryotes, dozens of MLOs have been identified, including the nucleolus, Cajal bodies, nuclear speckles, paraspeckles, promyelocytic leukaemia protein (PML) nuclear bodies, nuclear stress bodies, processing bodies (P bodies) and stress granules. MLOs contain specific proteins, of which many possess intrinsically disordered regions (IDRs), and nucleic acids, mainly RNA. Many MLOs contribute to gene regulation by different mechanisms. Through sequestration of specific factors, MLOs promote biochemical reactions by simultaneously concentrating substrates and enzymes, and/or suppressing the activity of the sequestered factors elsewhere in the cell. Other MLOs construct inter-chromosomal hubs by associating with multiple loci, thereby contributing to the biogenesis of macromolecular machineries essential for gene expression, such as ribosomes and spliceosomes. The organization of many MLOs includes layers, which might have different biophysical properties and functions. MLOs are functionally interconnected and are involved in various diseases, prompting the emergence of therapeutics targeting them. In this Review, we introduce MLOs that are relevant to gene regulation and discuss their assembly, internal structure, gene-regulatory roles in transcription, RNA processing and translation, particularly in stress conditions, and their disease relevance.

Remarkable improvement in detection of readthrough downstream-of-gene transcripts by semi-extractable RNA-sequencing.

The mammalian cell nucleus contains dozens of membrane-less nuclear bodies that play significant roles in various aspects of gene expression. Several nuclear bodies are nucleated by specific architectural noncoding RNAs (arcRNAs) acting as structural scaffolds. We have reported that a minor population of cellular RNAs exhibits an unusual semi-extractable feature upon using the conventional procedure of RNA preparation and that needle shearing or heating of cell lysates remarkably improves extraction of dozens of RNAs. Because semi-extractable RNAs, including known arcRNAs, commonly localize in nuclear bodies, this feature may be a hallmark of arcRNAs. Using the semi-extractability of RNA, we performed genome-wide screening of semi-extractable long noncoding RNAs to identify new candidate arcRNAs for arcRNA under hyperosmotic and heat stress conditions. After screening stress-inducible and semi-extractable RNAs, hundreds of readthrough downstream-of-gene (DoG) transcripts over several hundreds of kilobases, many of which were not detected among RNAs prepared by the conventional extraction procedure, were found to be stress-inducible and semi-extractable. We further characterized some of the abundant DoGs and found that stress-inducible transient extension of the 3'-UTR made DoGs semi-extractable. Furthermore, they were localized in distinct nuclear foci that were sensitive to 1,6-hexanediol. These data suggest that semi-extractable DoGs exhibit arcRNA-like features and our semi-extractable RNA-seq is a powerful tool to extensively monitor DoGs that are induced under specific physiological conditions.

tRNA-like Transcripts from the NEAT1-MALAT1 Genomic Region Critically Influence Human Innate Immunity and Macrophage Functions.

The evolutionary conserved NEAT1-MALAT1 gene cluster generates large noncoding transcripts remaining nuclear, while tRNA-like transcripts (mascRNA, menRNA) enzymatically generated from these precursors translocate to the cytosol. Whereas functions have been assigned to the nuclear transcripts, data on biological functions of the small cytosolic transcripts are sparse. We previously found NEAT1-/- and MALAT1-/- mice to display massive atherosclerosis and vascular inflammation. Here, employing selective targeted disruption of menRNA or mascRNA, we investigate the tRNA-like molecules as critical components of innate immunity. CRISPR-generated human ΔmascRNA and ΔmenRNA monocytes/macrophages display defective innate immune sensing, loss of cytokine control, imbalance of growth/angiogenic factor expression impacting upon angiogenesis, and altered cell-cell interaction systems. Antiviral response, foam cell formation/oxLDL uptake, and M1/M2 polarization are defective in ΔmascRNA/ΔmenRNA macrophages, defining first biological functions of menRNA and describing new functions of mascRNA. menRNA and mascRNA represent novel components of innate immunity arising from the noncoding genome. They appear as prototypes of a new class of noncoding RNAs distinct from others (miRNAs, siRNAs) by biosynthetic pathway and intracellular kinetics. Their NEAT1-MALAT1 region of origin appears as archetype of a functionally highly integrated RNA processing system.

Micellization: A new principle in the formation of biomolecular condensates.

Phase separation is a fundamental mechanism for compartmentalization in cells and leads to the formation of biomolecular condensates, generally containing various RNA molecules. RNAs are biomolecules that can serve as suitable scaffolds for biomolecular condensates and determine their forms and functions. Many studies have focused on biomolecular condensates formed by liquid-liquid phase separation (LLPS), one type of intracellular phase separation mechanism. We recently identified that paraspeckle nuclear bodies use an intracellular phase separation mechanism called micellization of block copolymers in their formation. The paraspeckles are scaffolded by NEAT1_2 long non-coding RNAs (lncRNAs) and their partner RNA-binding proteins (NEAT1_2 RNA-protein complexes [RNPs]). The NEAT1_2 RNPs act as block copolymers and the paraspeckles assemble through micellization. In LLPS, condensates grow without bound as long as components are available and typically have spherical shapes to minimize surface tension. In contrast, the size, shape, and internal morphology of the condensates are more strictly controlled in micellization. Here, we discuss the potential importance and future perspectives of micellization of block copolymers of RNPs in cells, including the construction of designer condensates with optimal internal organization, shape, and size according to design guidelines of block copolymers.

Triblock copolymer micelle model of spherical paraspeckles.

Paraspeckles are nuclear bodies scaffolded by RNP complexes of NEAT1_2 RNA transcripts and multiple RNA-binding proteins. The assembly of paraspeckles is coupled with the transcription of NEAT1_2. Paraspeckles form the core-shell structure, where the two terminal regions of NEAT1_2 RNP complexes compose the shell of the paraspeckle and the middle regions of these complexes compose the core. We here construct a theoretical model of paraspeckles by taking into account the transcription of NEAT1_2 in an extension of the theory of block copolymer micelles. This theory predicts that the core-shell structure of a paraspeckle is assembled by the association of the middle region of NEAT1_2 RNP complexes due to the multivalent interactions between RBPs bound to these regions and by the relative affinity of the terminal regions of the complexes to the nucleoplasm. The latter affinity results in the effective repulsive interactions between terminal regions of the RNA complexes and limits the number of complexes composing the paraspeckle. In the wild type, the repulsive interaction between the middle and terminal block dominates the thermal fluctuation. However, the thermal fluctuation can be significant in a mutant, where a part of the terminal regions of NEAT1_2 is deleted, and distributes the shortened terminal regions randomly between the shell and the core, consistent with our recent experiments. With the upregulated transcription, the shortened terminal regions of NEAT1_2 in a deletion mutant is localized to the core to decrease the repulsive interaction between the terminal regions, while the structure does not change with the upregulation in the wild type. The robustness of the structure of paraspeckles in the wild type results from the polymeric nature of NEAT1_2 complexes.

Impact of anatomical liver resection on patient survival in KRAS-wild-type colorectal liver metastasis: A multicenter retrospective study.

BACKGROUND: Liver resection is a standard therapy for colorectal liver metastasis. However, the impact of anatomical resection and nonanatomical resection on the survival in patients with Kirsten rat sarcoma-wild-type and Kirsten rat sarcoma-mutated colorectal liver metastasis remain unclear. We investigated whether anatomical resection versus nonanatomical resection improves survival in colorectal liver metastasis stratified by Kirsten rat sarcoma mutational status. METHODS: Among 639 consecutive patients with colorectal liver metastasis who underwent primary liver resection between January 2008 and December 2017, 349 patients were excluded due to their unknown Kirsten rat sarcoma mutational status, or due to receiving anatomical resection with concomitant non-anatomical resection, radiofrequency, or R2 resection. Accordingly, 290 patients with colorectal liver metastasis were retrospectively assessed. The relationships between resection types and survival were investigated in Kirsten rat sarcoma-wild-type and -mutated groups. RESULTS: Anatomical resection was performed in 77/186 (41%) and 44/104 (42%) patients with Kirsten rat sarcoma-wild-type and Kirsten rat sarcoma-mutated genetic statuses, respectively. For both, the clinical-pathologic factors were comparable, except a larger maximum tumor size and surgical margin were observed in anatomical resection cases. Anatomical resection patients had significantly longer recurrence-free survival and overall survival than nonanatomical resection cases in the Kirsten rat sarcoma-wild-type group (recurrence-free survival, P < .001; overall survival, P = .005). No significant recurrence-free survival or overall survival differences were observed between Kirsten rat sarcoma-mutated anatomical resection and non-anatomical resection (recurrence-free survival, P = .132; overall survival, P = .563). Although, intrahepatic recurrence in Kirsten rat sarcoma-wild-type and -mutated colorectal liver metastasis was comparable (P = .973), extrahepatic recurrence was increased in Kirsten rat sarcoma-mutated versus -wild-type colorectal liver metastasis (P < .001). CONCLUSION: In contrast to Kirsten rat sarcoma-mutated colorectal liver metastasis with higher extrahepatic recurrence after liver resection, local liver control via anatomical resection improved the postoperative survival in patients with Kirsten rat sarcoma-wild-type colorectal liver metastasis.

lncRNA Neat1 regulates neuronal dysfunction post-sepsis via stabilization of hemoglobin subunit beta.

Sepsis-associated encephalopathy (SAE) is characterized by acute and diffuse brain dysfunction and correlates with long-term cognitive impairments with no targeted therapy. We used a mouse model of sepsis-related cognitive impairment to examine the role of lncRNA nuclear enriched abundant transcript 1 (Neat1) in SAE. We observed that Neat1 expression was increased in neuronal cells from septic mice and that it directly interacts with hemoglobin subunit beta (Hbb), preventing its degradation. The Neat1/Hbb axis suppressed postsynaptic density protein 95 (PSD-95) levels and decreased dendritic spine density. Neat1 knockout mice exhibited decreased Hbb levels, which resulted in increased PSD-95 levels, increased neuronal dendritic spine density, and decreased anxiety and memory impairment. Neat1 silencing via the antisense oligonucleotide GapmeR ameliorated anxiety-like behavior and cognitive impairment post-sepsis. In conclusion, we uncovered a previously unknown mechanism of the Neat1/Hbb axis in regulating neuronal dysfunction, which may lead to a novel treatment strategy for SAE.