Search Results (3,557)

Rotenone, a classical inhibitor of mitochondrial complex I, disrupts electron transport and promotes the generation of reactive oxygen species (ROS), contributing to inflammation and cell death. However, the precise molecular mechanisms linking mitochondrial dysfunction to inflammatory signaling remain incompletely understood. In this study, we investigated the role of the cGAS–STING pathway in rotenone-induced NLRP3 inflammasome activation in PMA-differentiated THP-1 macrophages. Rotenone treatment activated the cGAS–STING axis, as evidenced by increased cGAS expression and the phosphorylation of STING and TBK1. This activation led to the nuclear translocation of NF-κB and the upregulation of NLRP3, promoting inflammasome priming and IL-1β secretion. Inhibition of STING using H-151 markedly suppressed NLRP3 expression, NF-κB activation, and IL-1β release. Similarly, cyclosporin A, an inhibitor of mitochondrial permeability transition pore opening, reduced mitochondrial ROS, cytosolic oxidized mitochondrial DNA, and downstream activation of the cGAS–STING pathway, thereby attenuating inflammasome activation. These findings demonstrate that rotenone activates the NLRP3 inflammasome via mitochondrial ROS-mediated release of mtDNA and subsequent activation of the cGAS–STING–NF-κB signaling axis in THP-1-derived macrophages. Full article

Monascus pigments (MPs), natural food colorants produced by Monascus spp., have been traditionally used in China and Southeast Asia. Our prior work demonstrated that altered cell wall architecture in M. purpureus M9 significantly enhances pigment synthesis and secretion, although biosynthetic regulation under combined cell wall stress and acidic conditions remains unexplored. This study employed comparative transcriptomics to investigate coordinated regulation of MP production by pH stress and modified cell wall polysaccharides in wild-type (M9-WT) and UDP-galactopyranose mutase-deficient (M9-KO) strains at pH 5.0 and 3.0. At pH 5.0, MpglfA knockout enhanced MP secretion through cell wall restructuring involving differential expression total 67 genes (DEGs) of primary metabolism. Acidic stress (pH 3.0) significantly increased DEGs (168 up/643 down) in M9-KO versus M9-WT, inducing amino acid/fatty acid degradation pathways that generate MP precursors (acetyl-CoA/propionyl-CoA) and accelerating metabolic transition toward secondary metabolism. Concurrently, M9-KO adopted survival strategies featuring growth suppression and acid stress pathway activation to coordinate osmotic adaptation. Glucan synthase genes exhibited greater pH sensitivity than galactomannan-related genes, while MP biosynthetic genes were transcriptionally repressed in M9-KO under higher acidity. KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment and the series test of cluster confirmed that primary metabolic pathways, particularly nitrogen/carbon metabolism, critically regulate MP biosynthesis. Transcriptomic analysis under limited pH regimes revealed that antagonistic regulators ROX1 and SPT15 mediated pH-responsive transcriptional reprogramming, potentially regulating specific MP biosynthesis (e.g., monascus orange pigments). This work established theoretical foundations for manipulating cell wall composition to enhance MP production efficiency. Full article

Background/Objectives: β-Carotene oxygenase-2 (BCO2) is a mitochondrial carotenoid-cleaving enzyme expressed in multiple tissues, including the lungs. While BCO2 regulates carotenoid handling, its role in shaping pulmonary immune architecture and antiviral responses is unknown. We hypothesized that BCO2 deficiency reprograms epithelial–innate circuits and alters antiviral outcomes. Methods: BCO2-knockout (KO) and C57BL/6J wild-type (WT) mice underwent lung single-cell RNA sequencing (scRNA-seq), immunoblotting, and intranasal SARS-CoV-2 challenge to assess cell-type heterogeneity, pathway programs (by gene set variation analysis, GSVA), and antiviral responses. Results: scRNA-seq resolved 14 major lung cell populations with cell-type-specific pathway shifts. Compared with WT, BCO2 KO lungs showed increased conventional dendritic cells and natural killer (NK) cells, with reductions in macrophages, B cells, and endothelial cells. In KO alveolar type II cells, GSVA indicated a stress-adapted metabolic program. Ciliated epithelium exhibited vitamin-K-responsive and axoneme-remodeling signatures with attenuated glucocorticoid and very-low-density lipoprotein remodeling. Innate lymphoid type 2 cells favored fatty acid oxidation and chromatin dynamics with reduced mitochondrial activity. NK cells were biased toward constitutive chemokine/cytokine secretion and counter-inflammatory signaling. Immunoblotting confirmed the elevated level of interferon regulatory factor-3 protein in BCO2-KO lungs. Functionally, BCO2-KO mice had improved outcomes after intranasal SARS-CoV-2 exposure. Conclusions: Loss of BCO2 reconfigures the pulmonary immune landscape and enhances antiviral responsiveness in mice. These findings identify BCO2 as a nutrient-linked enzyme with immunomodulatory impact and highlight cell-state changes as candidate mechanisms for improved antiviral tolerance. Full article

Fibroblasts determine repair quality during skin-wound healing. Our previous study found that Activin B promotes keratinocyte proliferation and migration, facilitating re-epithelialization. However, specific mechanisms governing fibroblast function during wound healing remain unclear. Here, we aimed to elucidate the mechanism by which Activin B regulates fibroblast activity during skin-wound healing. Using a murine skin-wound model, we performed hematoxylin-eosin, immunohistochemical, and Masson’s trichrome staining to evaluate Activin B’s effects on granulation tissue formation, angiogenesis, and collagen fiber synthesis. We assessed Activin B’s effects on fibroblast proliferation, migration, and collagen protein synthesis and investigated signaling pathway mechanisms in vitro. Animal experiments showed that Activin B accelerated wound healing by promoting granulation tissue regeneration and angiogenesis without affecting collagen fibers and Type I collagen synthesis. In vitro experiments demonstrated that Activin B modulates fibroblast proliferation and migration by activating JNK and ERK signaling pathways. Activin B may enhance angiogenesis by stimulating fibroblasts to secrete vascular endothelial growth factor, which induces dermal microvascular endothelial cell proliferation, promoting angiogenesis. Thus, we elucidated the dual regulatory paradigm of Activin B in fibroblasts; Activin B drives proliferation and migration via JNK/ERK signaling but does not directly regulate collagen synthesis. Full article

Background/objectives: Cellular senescence is a hallmark of aging that contributes to tissue dysfunction and age-related diseases. This process is characterized by the activation of the cyclin-dependent kinase inhibitor p16^INK4A and the secretion of pro-inflammatory factors collectively known as the senescence-associated secretory phenotype (SASP). In this study, we used human lung-derived cells, including A549 and IMR90 fibroblasts, to identify bioactive compounds from the roots of Liquidambar formosana that suppress p16^INK4A activity and attenuate SASP expression. Methods: Bioactivity-guided isolation was performed to obtain target compounds. The structures of the new compounds were elucidated using extensive 1D and 2D NMR spectroscopic analyses as well as high-resolution mass spectrometry. All isolated compounds were evaluated for their ability to inhibit p16^INK4A, a key regulator of the cell cycle and an important tumor suppressor protein. Results: Two previously undescribed monoterpenoids (1 and 2), characterized as cinnamic acid esters with a monoterpene-derived core, were isolated from the roots of L. formosana, along with six known compounds (3–8). Notably, compound 3 exhibited promising inhibition of p16^INK4A with an IC₅₀ value of 3.9 μM. Furthermore, this compound attenuated the senescence phenotype, as demonstrated by β-galactosidase staining and RT-qPCR analysis. This represents the first report identifying bioactive monoterpenoids from L. formosana that inhibit aging-related biomarkers such as p16^INK4A. Conclusions: These results suggest that cinnamic acid-conjugated monoterpenoids may serve as interesting lead structures for the development of agents targeting the p16^INK4A pathway for the treatment of aging-associated diseases. Further studies will be required to clarify the mechanisms of action of this compound and to evaluate its in vivo efficacy. Full article

The islet amyloid polypeptide (IAPP) is a 37-residue peptide hormone secreted by pancreatic β-cells that is known to aggregate into amyloid fibrils. These fibrils accumulate in the pancreatic islets of individuals afflicted with type 2 diabetes and are implicated in β-cell dysfunction. Metal ions such as copper and zinc are known to modulate IAPP fibrillization, yet the role of metal-induced oxidative modifications in this process remains largely unexplored. This study examines the non-enzymatic post-translational oxidation of IAPP and its effects on aggregation using the biologically relevant Cu/O₂/ascorbate system. Mass spectrometry identified residues within the amyloidogenic region (residues 20–29) as the primary targets of oxidation. These oxidative modifications impaired the formation of cross-β-sheet amyloid fibrils and promoted the accumulation of amorphous aggregates. The H18A IAPP derivative, lacking the key metal-binding histidine, was also examined to assess the impact of sequence variation on oxidation and aggregation. Copper-mediated oxidation of H18A resulted in a broader distribution of oxidation sites and impacts fibril formation. These findings provide preliminary mechanistic insights into copper-induced oxidation and its impact on IAPP aggregation pathways. Full article

Glucagonoma, a rare neuroendocrine tumor, lacks targeted treatment drugs. Excessive secretion of glucagon is the main cause of its clinical syndrome. To explore targeted therapeutic drugs that can inhibit glucagon secretion and tumor proliferation, we investigated the effect of Trametenolic Acid (TA) on mouse pancreatic alpha TC1 clone 6 (αTC1-6) cells and its regulatory role in the PI3K/AKT signaling pathway. Cell viability of αTC1-6 cells was assessed via the MTT assay. Glucagon content in cell culture supernatants was measured using an Enzyme-Linked Immunosorbent Assay (ELISA). Autophagic vacuoles were visualized through Monodansylcadaverine (MDC) staining. The expression of autophagy-related proteins including Atg7, LC3 Ⅱ and PI3K/AKT signaling pathway-related proteins mTOR and FoxO1 were determined by Western blot. The results showed that the proliferation of αTC1-6 cells was significantly inhibited by TA in a dose- and time-dependent manner, and the IC₅₀ was 140.71, 26.77 and 1.99 μM after treatment of 12, 24, and 48 h, respectively. The secretion of glucagon was significantly inhibited by TA. The MDC staining results showed that the fluorescent labeled autophagic vesicles in the TA group were increased. The Western blot results showed that the expression of Atg7 and LC3 Ⅱ was promoted by TA in a dose-dependent manner, the phosphorylation of PI3K, AKT, mTOR and FoxO1 was significantly inhibited, and the expression of FoxO1 protein was increased. These results demonstrated that TA can inhibit glucagon secretion, induce autophagy, and suppress cell proliferation in αTC1-6 cells. The mechanism may be associated with the PI3K/AKT signaling pathway. Full article

Excretory/secretory products from parasites (ESPs) can act as pathogen-associated molecular patterns (PAMPs) to activate innate immunity. Parasites may achieve immune evasion by modulating the interaction between PAMPs and the nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing three (NLRP3) inflammasome. Previous studies have suggested that some components of ESPs from Clonorchis sinensis (CsESPs) can induce the host’s immune responses, but the components that balance immunopathology and maintain chronic infection in chronic Clonorchis sinensis (C. sinensis) remain unclear. We previously found that the iNOS-interacting protein from C. sinensis (CsNOSIP), a component of CsESP, stimulates macrophages to produce reactive oxygen species (ROS) and nitric oxide (NO), both of which inhibit NLRP3 inflammasome activation. Therefore, this study investigated the effects of CsESP and CsNOSIP on inflammasome activation using RT-PCR, Western blot, and ELISA. This study showed that CsESPs promoted NLRP3 inflammasome activation in RAW264.7 cells, while CsNOSIP inhibited LPS-induced IL-1β secretion through an NLRP3-caspase-1-dependent pathway and reversed the CsESPs-induced activation through the iNOS/NO–NF-κB pathway. These results reveal the antagonistic effects of CsESPs and CsNOSIP in inflammasome regulation, suggesting that this balance contributes to the regulation of the host’s immunity and the promotion of chronic infection of C. sinensis, providing potential targets for prevention and treatment. Full article

Reproductive and growth traits are key economic traits in sheep. This study aims to identify key single nucleotide polymorphisms (SNPs) and candidate genes associated with reproductive and growth traits in Tianmu polytocous sheep through a genome-wide association study (GWAS). The findings are expected to provide both a theoretical foundation for molecular breeding in this breed and novel insights into the genetic basis of ovine reproductive and growth performance. This study took 483 adult Tianmu polytocous ewes as the research subjects, collected their lambing records, measured their phenotypic values of growth traits (3 weight and 11 body size traits), and collected their blood samples for whole-genome resequencing to identify SNPs in the Tianmu polytocous sheep genome. The results identified a total of 9,499,019 (3× coverage) and 27,413,216 (30× coverage) high-quality SNPs in the Tianmu polytocous sheep genome. Subsequently, the association analysis between SNPs and reproductive and growth traits was conducted using a mixed linear model. A total of 92, 66, 18, 28, 6, 42, 3, 3, 6, 1, 12, 3, 22, 8, 6, and 3 SNPs were found associated with litter size at first parity, litter size at second parity, litter size at third parity, litter size at fourth parity, birth weight, weaning weight, body height, withers height, body length, head length, head width, cannon bone circumference, forelimb height, chest girth, chest depth, and withers width, respectively. Further, based on SNP annotation, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, candidate genes associated with the reproductive and growth traits were identified. Among these genes, 11 LOC, DEPTOR, GNG12, GRM7, PTH, PTH2R, WWOX, INHA, and NRG3 are candidate genes associated with litter size at first parity or litter size at third parity. These genes are involved in the G protein-coupled receptor signaling pathway, G protein-coupled receptor activity, ovarian tissue development, and hormone secretion. Additionally, TFRC and NTN1 are candidate genes associated with birth weight, while five UGT1A and CASR are candidate genes associated with weaning weight. These candidate genes are primarily involved in lipid metabolism. Finally, the following genes were identified as candidates associated with specific traits: DLG2, TMEM126A, and TMEM126B with body height; DSCAM and SCN8A with body length; BARX1 with cannon bone circumference; four LOC genes with forelimb height; EPHA4 with chest depth; and MRS2 with withers width. Full article

This study investigated the interactive effects of dietary vitamin A (VA) and all-trans retinoic acid (ATRA) on growth performance and intestinal health in broilers. A total of 432 one-day-old male Arbor Acres chicks were assigned to a 2 × 3 factorial design with two VA levels (2000 and 6000 IU/kg) and three ATRA levels (0, 0.25, and 0.50 mg/kg). The maize–soybean meal basal diet contained 180 IU/kg VA without extra VA supplementation. Results showed that compared with 0 mg/kg ATRA, 0.50 mg/kg ATRA enhanced average daily gain (ADG) during days 1–21 (p < 0.05). Compared with 2000 IU/kg VA, 6000 IU/kg VA improved body weight on day 35 as well as ADG and feed intake during days 22–35 and reduced feed conversion ratio over the entire trial (p < 0.05). There were VA × ATRA interactions for the ratio of villus height (VH) to crypt depth (CD) in duodenum as well as VH and CD in ileum on day 21 (p < 0.05). The 0.25 mg/kg ATRA decreased duodenal VH/CD and ileal VH in broilers fed 2000 and 6000 IU/kg VA, respectively (p < 0.05). The 0.50 mg/kg ATRA increased ileal VH in broilers fed both 2000 and 6000 IU/kg VA (p < 0.05). When birds were fed 6000 IU/kg VA, 0.50 mg/kg ATRA increased ileal CD compared with 0.25 mg/kg CD (p < 0.05). On day 35, compared with 0 mg/kg ATRA, 0.25 mg/kg ATRA increased ileal VH while 0.50 mg/kg ATRA decreased ileal CD, and both of them increased ileal VH/CD (p < 0.05). The VA × ATRA interactions for mRNA expression of jejunal Mucin5ac on day 21 and jejunal Occludin, Claudin-1, Mucin 2, leucine-rich-repeat-containing G-protein-coupled receptor 5⁺ (Lgr5⁺), zinc and ring finger 3 (Znrf3), and secreted phosphoprotein 1 (SPP1) on day 35 were detected (p < 0.05). Dietary 0.50 mg/kg ATRA up-regulated jejunal Mucin5ac expression in broilers fed 6000 IU/kg VA on day 21 as well as Claudin-1, Znrf3, and SPP1 expression broilers fed 2000 IU/kg VA on day 35 (p < 0.05). The 0.25 mg/kg ATRA down-regulated Occludin expression in broilers fed 6000 IU/kg VA on day 35 (p < 0.05). The 0.25 mg/kg ATRA decreased and increased Lgr5⁺ expression on day 35 in broilers fed 2000 and 6000 IU/kg VA, respectively (p < 0.05). Both 0.25 and 0.50 mg/kg ATRA down-regulated Mucin-2 expression in broilers fed 2000 IU/kg VA on day 35 (p < 0.05). The VA × ATRA interactions were observed for jejunal retinol dehydrogenase 10 (RDH10), cytochrome P450, family 26, subfamily A, polypeptide 1 (CYP26A1), retinoic acid receptor (RAR) α, and RARβ expression on days 21 and 35 (p < 0.05). Both 0.25 and 0.50 mg/kg up-regulated RDH10, CYP26A1, and RARβ expression in broilers fed 6000 IU/kg VA (p < 0.05). The RARα expression was up-regulated by 0.50 and 0.25 mg/kg ATRA on days 21 and 35, respectively (p < 0.05). Plasma metabolomics identified 269 VA- and 185 ATRA-associated differential metabolites, primarily enriched in lipid metabolism, vitamin digestion and absorption, and bacterial infection pathways. In conclusion, dietary 0.50 mg/kg ATRA and 6000 IU/kg VA enhanced growth performance, intestinal integrity, and VA metabolism, partly through activation of retinoic acid receptors and modulation of plasma lipid metabolism. Full article

Caffeic acid (CA), 3-O-caffeoylquinic acid (3-CQA), and 5-O-caffeoylquinic acid (5-CQA) were subjected to treating stimulated mouse P815 mast cells to unravel their antiallergic potential. β-Hexosaminidase release, appearance, morphology change, cytokine secretions, and degranulation-related pathway gene expressions, including Mas-related G protein-coupled receptor, member B2 (MRGP receptor B2), and inositol 1,4,5-triphosphate receptor 2 (IP3 receptor 2), in the stimulated mast cells were measured. An ELISA was used to determine the secreted cytokines. The relative gene expression folds were analyzed with reverse transcription real-time quantitative polymerase chain reaction. Correlations between gene expressions and different parameters were analyzed using the Pearson product–moment correlation coefficient (r). The results showed that CA had a superior effect than 3-CQA and 5-CQA on reducing β-hexosaminidase release, IL-4, and IL-6 cytokine secretions by the compound 48/80 (C48/80)- and 5-hydroxymethyl-2-furaldehyde (5-HMF)-stimulated mast cells. CA increased intact mast cell numbers but reduced granule releases, evidencing that CA may soothe activated mast cells. CA reduced IP3 receptor 2 gene expression. There were positive correlations between IP3 receptor 2 gene expression and IL-4 and IL-6 cytokine secretions. Our results conclude that CA might inhibit degranulation, IL-4 and IL-6 cytokine secretions, and IP3 receptor 2 gene expression in C48/80-stimulated mouse P815 mast cells. Full article

The global demand for processed foods has increased reliance on synthetic phenolic antioxidants (SPAs), including tert-butylhydroquinone (TBHQ), a widely used additive to prevent lipid oxidation and extend shelf life. TBHQ is considered safe at present regulated levels; however, studies suggest potential adverse effects, including oxidative stress, genotoxicity, and impacts on immune function, raising concerns about human health and ecological risks. Herein, we investigated the immunomodulatory effects of TBHQ on RAW 264.7 murine macrophages pre-exposed to 0.1, 1, and 5 µM TBHQ and then stimulated with lipopolysaccharide (LPS) or polyinosinic-polycytidylic acid (poly I:C, PIC) to model bacterial and viral immune challenges. We then used functional assays and transcriptomic profiling to assess inflammatory responses and oxidative stress signaling. TBHQ reduced nitric oxide production and IL-10 secretion at the highest non-cytotoxic dose, and enhanced phagocytosis and IL-6 secretion at the lowest concentrations. Overall, transcriptomics revealed significant downregulation of proinflammatory pathways and induction of glutathione and xenobiotic metabolism. Pre-treatment with TBHQ increased gene transcript counts of key metabolic genes/transporters such as Cbr3, Adh7, Gstp1/3, Gsta3, Hmox1 and Gclm. Following treatment with LPS or PIC several genes for classical proinflammatory chemokines and cytokines such as Cxcl2, Ccl2, Ccl12, Acod1, Ptgs2, Nos2, and Il6 were downregulated. Genes involved in NF-κB signaling, such as Nfkbia, Nfkb1, and Ikbke were also downregulated. Our study suggests that the induction of Nrf2-related antioxidant pathways by TBHQ is the main driver for reduced inflammatory signaling in macrophages. Full article

The primary cilium is generally viewed as a sensory organelle that transduces chemical and mechanical stimuli from the environment. In the adult hippocampus, primary cilia mediate the effects of sonic hedgehog (Shh) and other signals on neurogenesis and hippocampal function, and loss of cilia leads to cognitive and behavioral deficits. The secreted peptide noggin is a bone morphogenetic protein (BMP) antagonist and plays a critical role in regulating adult hippocampal neurogenesis (AHN) and hippocampus-dependent behavior. Here, we show that noggin is expressed by mature granule cell neurons, that it is apically targeted and localized intracellularly near the pocket region of primary cilia, and that cilia regulate noggin release through Shh and somatostatin (SST) pathways. Further, granule cell activation modulates noggin dynamics both in vitro and in vivo. Together, these findings demonstrate synergy between Shh and noggin and the positive regulatory action of neuronal activity on regulating BMP antagonism within the neurogenic niche. Thus, the primary cilium is not only an organelle that transduces signals to neurons but also one that mediates extracellular signaling. Significance statement: Primary cilia are organelles that protrude from the surface of most vertebrate cell types. Defects in primary ciliary structure and function are associated with human disease. Primary cilia are generally viewed as exclusively sensory organelles that respond to environmental signals to regulate both cell development and adult cell function. This study demonstrates that the primary cilia in hippocampal granule cell neurons mediate the release of the BMP antagonist, noggin. These observations expand the current understanding of ciliary signaling and may inform future studies exploring the connection between hippocampal activity and cognition in ciliopathies. Full article

Autoimmune diseases are chronic inflammatory conditions characterized by the breakdown of immune tolerance to self-antigens. While genetic and environmental factors play key roles, growing evidence highlights chronic stress as a significant contributor to immune dysregulation through its impact on the hypothalamic–pituitary–adrenal (HPA) axis. The HPA axis, primarily via cortisol secretion, serves as the major neuroendocrine mediator of stress responses, influencing both immune regulation and systemic homeostasis. This review synthesizes current literature on HPA axis physiology, the mechanisms of cortisol signaling, and the maladaptive effects of chronic stress. Emphasis is placed on clinical and experimental findings linking HPA dysfunction to immune imbalance and autoimmunity, as well as organ-specific consequences across neuroimmune, endocrine, cardiovascular, gastrointestinal, integumentary, and musculoskeletal systems. Chronic stress leads to impaired HPA axis feedback, glucocorticoid receptor resistance, and paradoxical cortisol dysregulation, fostering a pro-inflammatory state. This dysregulation promotes cytokine imbalance, weakens protective immune mechanisms, and shifts the immune response toward autoimmunity. Evidence from both human and animal studies associates persistent HPA dysfunction with diseases such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. HPA axis dysregulation under chronic stress constitutes a critical mechanistic link between psychological stress and autoimmune disease. Understanding these pathways provides opportunities for therapeutic interventions, including stress management, lifestyle modification, and neuroendocrine-targeted treatments. Future research should focus on multi-omics and longitudinal approaches to clarify the reversibility of HPA alterations and identify resilience factors. Full article

In-depth exploration of tumor immune suppression mechanisms may provide new therapeutic options for NF2-associated tumors. In this study, we found that sEVs secreted by NF2-associated schwannomas (NF2-EVs) facilitate the conversion of CD14⁺ monocytes into an MDSC-like phenotype, showcasing MDSC-like inhibitory functions. Moreover, these NF2-EVs are capable of enhancing tumor cell proliferation. Through proteomic analysis and subsequent validation of the NF2-EVs, we identified elevated levels of HSP90. When we knocked down HSP90 expression in tumor cells, the sEVs secreted showed diminished capacity to convert monocytes into MDSCs and a reduced ability to promote tumor cell proliferation. Conversely, sEVs secreted by tumor cells that overexpress HSP90 displayed the opposite effects. Further mechanistic studies revealed that HSP90 could influence the expression of AKT/p-AKT and ERK/p-ERK. Our results suggest that NF2 tumor cells could regulate the AKT/p-AKT and ERK/p-ERK pathways to promote tumor cell proliferation and the formation of an immunosuppressive microenvironment by secreting sEVs’ HSP90, offering valuable insights into the involvement of HSP90 in exosome-mediated communication within the context of NF2-related schwannomatosis (NF2-SWN). This information has the potential to inform the design of effective immunotherapeutic protocols and offer new treatment options for NF2-SWN patients. Full article