Abstract Background Noise exposure is an environmental stressor associated with cognitive impairment. Workers in specific work environments are often exposed to around-the-clock noise and experience severe emotional and cognitive dysfunctions associated with neuropathology similar to Alzheimer’s disease. However, the underlying neural mechanisms have not been extensively investigated. Methods The molecular pathways underlying cognitive impairment following around-the-clock noise exposure were evaluated using male Wistar rats. The open-field and Morris water maze tests were used to assess cognitive performance. RNA sequencing was employed to identify key regulators and pathological pathways of cognitive impairment. Histological changes were observed using hematoxylin and eosin staining, Nissl staining, transmission electron microscopy, and immunofluorescence. Western blotting was performed to detect altered apoptotic markers. Results Around-the-clock noise exposure significantly induced cognitive decline and neuronal damage in rat. Transcriptome sequencing of hippocampal tissues from control and noise-exposed rats revealed that the expression of the serum/glucocorticoid regulated kinase 1 (SGK1) gene was reduced, with a corresponding decrease in its protein levels. Moreover, this dysregulation led to the inhibition of the intracellular PI3K/SGK1/Foxo3 pathway, triggering the upregulation of the apoptotic proteins Bcl-2, Bax, Fasl, and TRAIL. Conclusions These findings suggest that around-the-clock noise exposure induces hippocampal neuronal apoptosis, thus exacerbating cognitive impairment. This elucidates the potential role of the PI3K/SGK1/Foxo3 pathway in noise-induced neuronal damage. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-025-06501-7. Keywords: Around-the-clock noise, Apoptosis, Cognitive impairment, Serum/glucocorticoid regulated kinase 1 Introduction The diversity and complexity of occupational environments result in workers being constantly exposed to noise, which may lead to hearing loss, cardiovascular disorders, and neuroimmune disorders [[40]1–[41]5]. As a special occupational group, military service members often live in environments with little time to recover from hazardous noise. Their exposure to various noise sources averages more than 12 h, and the 24-h equivalent continuous sound level (24-h) can approach 100 dB [[42]6]. This exposure affects their ability to perform cognitively relevant tasks and missions. Epidemiological evidence supports the correlation between long-term environmental noise exposure and exacerbated cognitive impairment, higher risk of mental diseases, and dementia [[43]7–[44]9]. It has been demonstrated that noise exposure primarily affects the central nervous system and that brief exposure to noise conditions may lead to neurological and cognitive impairment [[45]10]. Moreover, experimental evidence in animals collectively points to a correlation between chronic exposure to noise and cognitive dysfunction, which often coincides with the neuropathological profile of Alzheimer’s disease (AD) [[46]3, [47]11–[48]13]. Unlike the noise exposure of an 8-h workday, around-the-clock noise exposure patterns in long oceangoing voyages may impair physiological repair and compensatory functions, leading to a cumulative negative impact on the nervous system. Our previous studies showed that apoptosis may be a pathological mechanism underlying noise-induced nervous system damage [[49]14] and that around-the-clock noise exposure adversely affects autophagic flux homeostasis and contributes to AD-like neuropathological changes in the cortex and hippocampus [[50]15]. Autophagy and apoptosis are controlled by multiple common upstream signals, and these processes cross-regulate each other, playing important roles in the development of the organisms, maintenance of tissue homeostasis, immune response, and disease defense [[51]16–[52]19]. Generally, autophagy blocks the induction of apoptosis, whereas the activation of apoptosis-related caspases inhibits autophagy [[53]20]. Acute and chronic noise exposure can cause pathological outcomes such as neuronal apoptosis [[54]14, [55]21], which may result from misfolded pathological neurofibrillary tangle tau and β-amyloid in the hippocampus and the prefrontal cortex, ultimately leading to neurocognitive deficit [[56]22]. The literature highlights significant gaps in our understanding of how around-the-clock noise exposure in noisy environments leads to hippocampal neuronal apoptosis and the subsequent deposition of cognitive impairment markers. This gap highlights the need for more detailed investigations to elucidate the complex interactions between environmental noise and brain pathology. This study adopted a multifaceted approach using behavioral assessment, histological analysis, and advanced transcriptomic techniques to investigate cognitive deficits associated with around-the-clock noise exposure. The main objective of this study was to elucidate the mechanisms by which chronic exposure to environmental noise leads to cognitive dysfunction, with a particular focus on dysregulation of the PI3K/SGK1/Foxo3 signaling pathway and its role in neuronal apoptosis. By deepening our understanding of these mechanisms, this study aims to facilitate the development of targeted interventions to mitigate the cognitive effects of noise exposure in occupational settings. Materials and methods Animals and experimental groups Twenty male Wistar rats (weight: 180–200 g) were randomly divided into a control group and a 24-h noise exposure group. The rats were obtained from Beijing Viton Lihua Laboratory Animal Technology Co. The rats were housed at a normal condition with an ambient temperature of 23 ± 2 °C and had free access to standard laboratory rodent food and water. Subsequently, the rats were anaesthetised and their brains were collected after sacrifice and individually sampled for molecular biology monitoring and analysis (Fig. [57]1). All experiments were conducted as per Guidelines approved by the Animal and Human Use Research Committee of the Tianjin Institute of Health and Environmental Medicine (TIHEM) and in accordance with the ‘Three Rs’ principle. Fig. 1. [58]Fig. 1 [59]Open in a new tab Schematic representation of the procedural flow of the experiment, encompassing model establishment, model evaluation, grouping, and subsequent processing Noise exposure set-up Before noise exposure, all rats were acclimatized to the new experimental environments, including the noise exposure room and soundproof room, for a week. For the noise-exposure model, rats in noise exposure group were transferred into customized noise exposure cages and exposed to noise stimulation. To simulate the noise intensity and exposure pattern of a military operational environment, the noise exposure conditions were set to 95 dB white noise during the day 8 h/d (8:00–16:00) and 75 dB white noise at night 16 h/d (16:00–8:00 the next day) for 40 days. A noise generator (BK 3560 C, B&K Instruments, Nærum, Denmark) was used to generate white noise, which was amplified using a power amplifier and broadcast through a loudspeaker (IBO, BA-215, China) inside a soundproof room. The animals were housed in individual wired cages and placed under an amplifier. Sound levels inside the cages were measured hourly with a sound level meter (BSWA, 308, China) at the rat’s ear position. The difference in the noise levels between the different cages was < 2 dB. Control rats were moved into the soundproof room (background noise not exceeding 45 dB) for the same period as that of the noise exposure group rats. Behavior test Open-field test (OFT) Examine the living-conditions of the rats at least 5 days prior to the test to ensure that the standard guidelines are met. On the day of the test, the animals were allowed to acclimatise to the test environment for 30–60 min. The animals were then transferred to the OFT area. The test site was divided into 16 zones, with the middle 4 zones designated as the centre zone. Each rat was placed in the same position for 5 min. The total distance travelled by each rat and the time spent in the central area were recorded using VisuTrack software. Morris water maze (MWM) The MWM test was performed after the noise intervention period to assess the spatial learning and memory abilities of rats. The apparatus employed for the test was a 1.6 m diameter, 0.5 m high pool of water, which was divided into four discrete quadrants. At the centre of this structure was a target platform with a 1 cm shelter below the water surface. Throughout the experiment, we created an environment that stabilised the water temperature at 23 °C ± 2 °C and provided tranquillity to minimise disruptive changes. Importantly, we removed the main external light source around the pool. During the training trials, rats were systematically introduced to the quadrant on the opposite side of the platform each day. Rats were considered to have successfully located the platform when they found and climbed onto the platform within one minute and maintained their position for at least 2 s. The rats were then given 10 s to memorise the spatial coordinates relative to the platform. Western blotting analysis Hippocampal tissues from the rats were lysed using radioimmunoprecipitation assay lysis buffer, followed by quantification of the total protein concentration using the bicinchoninic acid (BCA) protein assay. The isolated proteins were electrophoresed on 8% and 10% SDS-PAGE gels, followed by denaturation with SDS loading buffer before being transferred onto polyvinylidene fluoride (PVDF) membranes. The membranes were blocked with 5% nonfat milk for 1 h at ambient temperature. After blocking, the membranes were incubated overnight at 4 °C with primary antibodies, including cleaved caspase-3 (1:500, CST/9664#, USA), caspase-3 (1:1000, A2156,, ABclonal, China), Bcl-2 (1:1000, A0208, ABclonal, China), Bax (1:500, ab32503, Abcam), caspase-12 (1:1000, A22864, ABclonal, China), PI3K ( 1:1000, A18675, ABclonal, China ), phospho-Akt (1:1000, AP1453, ABclonal, China ), PDK1 (1:1000, A21810, ABclonal, China), phosopho-PDK1 (1:1000, #[60]O15530, CST, USA), FOXO3 (1:1000, A0102, ABclonal, China), phospho-FOXO3 (1:1000, AP0856, ABclonal, China), SGK1 (1:400, A1025, ABclonal, China), Bcl-6 (1:1000, A7173, ABclonal, China), Bim (1:1000,A19702, ABclonal, China), FasL (1:500, ab82419, abcam, USA), and TRAIL (1:1000, A25394, ABclonal, China).The following day, the secondary antibody (1:10,000, ABclonal, China), labeled with an infrared fluorescent dye, was applied and incubated for 1 h, and the bands were visualized using an electrochemiluminescent solution. Transmission electron microscopy Three rats in each group were executed. Hippocampal tissues were harvested, dissolved in 2.5% glutaraldehyde in cacodylate buffer, dehydrated with an ethanol gradient, rendered transparent with xylene, immersed in p-xylene, and cooled to -20 °C. Thin slices (50 nm) of the tissue were examined on a copper grid using a TECNAI G 20 TWIN electron microscope (FEI, Hillsboro, OR, USA) and double-stained with a saturated aqueous solution containing 2% uranyl acetate and 2% lead citrate. Hematoxylin-eosin (HE) staining, Nissl staining, and Immunofluorescence For HE staining, sections approximately 4 μm thick underwent the following staining procedure: hematoxylin staining for 5 min, rinsing with water until the appearance of blue color, eosin staining for 3 min, dehydration, sealing, air-drying, and observation under an optical microscope. The slides were air-dried at room temperature(24℃±2℃) for at least 60 min before Nissl staining. Sections were rinsed twice with 10 mM phosphate-buffered saline for 5 min and double-distilled water (ddH[2]O) for 1 min. The sections were then immersed in a Nissl staining solution for 20 min. After staining, two additional rounds of ddH[2]O rinsing were performed for 5 min each. The slides were subjected to a series of ethanol and xylene treatments: first in 90% ethanol for 3 min, then in 95% ethanol for 3 min, followed by two treatments lasting 3 min each, and finally three treatments with pure (100%) xylene for 3 min each. The sections were sealed with neutral gum and observed under optical microscope (Nikon Eclipse E100,Japan) [[61]23], all brain slices were digitally scanned using an automated slice scanning system (3D HISTECH, Hungary) and analysed in ImageJ. Sections for immunofluorescence measured approximately 4 μm in thickness and were placed in an immunoreactivity enhancement solution and microwaved for 15 min. After cooling and washing, the sections were blocked with bovine serum albumin (BSA) for 30 min. Caspase-3 (1:2000, GB11532, Servicebio, China), Bcl-2 (1:3000, [62]GB114830, Servicebio, China), SGK1 (1:200, Proteintech, USA), and Foxo3 (1:200, K00157P, Solarbio, China) antibodies were incubated overnight at 4 °C for 50 min with the corresponding secondary antibodies. Thereafter, a 10-min 4′,6-diamidino-2-phenylindole (DAPI) staining procedure was performed. After washing, the slides were sealed with tablets to prevent fluorescence quenching, and images were acquired using a fluorescence microscope (NIKON, Japan). Real-time quantitative PCR (qPCR) RNA was extracted using a test kit (RNAiso Plus, Takara, Japan) following the steps outlined in the manufacturer’s protocol. The extracted RNA was diluted in RNase-free ddH2O. After extraction, reverse transcription was performed using a reverse transcription kit (Takara, Japan) following the manufacturer’s guidelines. The primer sequences for the SGK1 gene were as follows: (F) CAAATATCGGGGCGATGACCGTCA; (R) AGTGAAGGCCCACCAGGAAAG; GAPDH: (F) GACAACTTTGGCATCGTGGA; (R) ATGCAGGGATGATGATGTTCTGG. RNA sequencing and bioinformatics analysis Three rats were selected from each group, and mRNA was extracted and purified from the hippocampal tissues using the Dynabeads mRNA Purification Kit (Invitrogen, 61,006) according to the manufacturer’s instructions. The mRNA from each rat was fragmented to construct a cDNA library and then sequenced. The cDNA library was sequenced using an Illumina HiSeq 4000 sequencing platform. Significantly differentially expressed mRNAs with an adjusted false discovery rate of < 0.05 were identified. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. Protein-protein interactions (PPIs) of differentially expressed proteins were identified using the online database STRING 12.0 and Cytoscape software. Pathway enrichment analysis of the differentially expressed genes (DEGs) was performed using Wei Sheng Xin software ([63]http://www.bioinformatics.com.cn) [[64]24]. All RNAseq data was uploaded to China National Center for Bioinformation (CNCB) ( [65]https://www.cncb.ac.cn/), and the assigned accession of the submission is: CRA024501 ([66]https://bigd.big.ac.cn/gsa/browse/CRA024501). Statistical analysis Data are presented as mean ± standard error of the mean (SEM). Statistical analysis was performed using the SPSS 22.0 software (SPSS Inc., Chicago, IL, USA) and GraphPad Prism 8 (GraphPad Software, San Diego, CA, USA). The Student’s t-test was used to determine the statistical significance. Statistical significance was set at p < 0.05. Results Noise exposure leads to a decline in cognitive performance and causes damage to hippocampal neurons We established a rat model to explore the mechanism of cognitive impairment induced by around-the-clock noise exposure. Based on this model, we assessed learning and memory abilities by performing the open-field and Morris water maze tests [[67]25, [68]26]. We then characterized the tissue damage by gross anatomical sections and ultrapathological electron microscopy observations and further searched for and verified key molecular expression changes by RNA sequencing and molecular biology experiments (Fig. [69]1). To examine the effect of noise on locomotor activity, the rats were assessed using an open-field test. Around-the-clock noise affected the total travel distance and influenced the time spent in the central arena in the noise-exposed group compared to that in the control group, suggesting that noise negatively impacts animal locomotive behaviors (Fig. [70]2A-B). Next, we assessed the effects of noise on cognitive impairment using the Morris water maze test. Despite a decrease in both the time and path length required to locate the hidden platform over 6 days of training for all animals, the around-the-clock noise group exhibited a significantly prolonged latency compared to that in the control group (Fig. [71]2C). Additionally, in the spatial exploration experiment, rat in the around-the-clock noise group showed a significant reduction in the percentage of time and distance spent swimming in the platform quadrant and in the number of times they crossed the target platform (Fig. [72]2D-E). These phenomena suggest that noise exposure significantly impairs cognitive function. Fig. 2. [73]Fig. 2 [74]Open in a new tab Around-the-clock noise exposure leads to a decline in cognitive performance. (A) Open-field behavior test: Total track route. (B) Total central square traveled distance, entries in the central square, and total central square time. (C) Latency in the orientation navigation test. (D) Trajectory map in the spatial probe test. (E) Times of platform crossing in the spatial probe test. (F) Time spent in target quadrant. (G) Percentage of time/distance of rat swimming in the platform quadrant. n = 6, Values are expressed as means ± SEM.*p < 0.05, **p < 0.01 Around-the-clock noise exposure induces morphological and structural alterations in hippocampal neurons and the appearance of apoptotic markers capase-3 and Bcl-2 Next, we examined the apoptotic morphology in the hippocampus of rats exposed to noise for 24 h using TEM. Endoplasmic reticular expansion, increased nuclear chromatin density, and mitochondrial vacuolization were observed in the hippocampus of rats exposed to around-the-clock noise; however, they were not detected in the control rats (Fig. [75]3A). Furthermore, thioflavine S staining showed that noise exposure led to the deposition of the cognitive impairment marker Aβ amyloid and the pathological changes are marked by red arrows (Figure [76]S1A). We then examined the effects of noise on morphological changes in hippocampal neurons. Neurons in the hippocampal region were aligned and compact, as observed through HE and Nissl staining. No obvious cell loss was observed in the control group, and the neurons had clear nuclei. In contrast, neurons in the noise-exposed group were less structurally organized, with poorly defined cell boundaries, condensed nuclei, and inconspicuous nucleoli (Fig. [77]3B-C). These findings were further confirmed via immunofluorescence analysis (Fig. [78]3D-E). Next, we investigated the effect of noise exposure on the expression of apoptotic marker proteins. Western blotting results showed that the expression of caspase-12, and Bax was significantly increased and the expression of Bcl-2 was significantly decreased, while the expression of cleaved caspase-3 also showed an increasing trend, but there was no significant difference in caspase-3 in the hippocampus after noise exposure. Immunofluorescence results further confirmed these findings (Fig. [79]3F-J, Figure [80]S1B). Collectively, these data suggest that exposure to around-the-clock noise leads to the onset of apoptosis. Fig. 3. [81]Fig. 3 [82]Open in a new tab Exposure to around-the-clock noise triggers neuropathological changes in the hippocampus. (A). Ultrastructural hippocampal changes were observed via transmission electron microscopy, Scale bar = 1 μm. n = 3. (B)-(C). Hematoxylin and eosin (HE) and Nissl staining, Scale bar = 100 μm. n = 3. (D)-(E). Immunofluorescence staining was used to determine the alterations in caspase-3 and Bcl-2, Scale bar = 100 μm. n = 3. F-J. Representative western blot bands of apoptosis related proteins in the hippocampus of rats. n = 3.Values are expressed as means ± SEM.* p < 0.05 RNA-transcriptome analysis revealed that noise exposure induces SGK1 downregulation in hippocampal tissues To investigate the precise mechanism of noise-induced cognitive damage, we conducted transcriptome sequencing to identify key molecular and signaling pathways. Principal component analysis indicated two principal components of variation. Two clusters were identified, corresponding to the control and noise-exposed groups (Figure [83]S2A). The volcano plot revealed differential gene expression, identifying 255 DEGs (log[2] [fold change] ≥ 1 and p < 0.05). Among these, 47 genes were significantly upregulated, whereas 208 were downregulated, among which SGK1 exhibited the most significant downregulation after noise exposure (Fig. [84]4A). Next, we briefly listed the significantly downregulated DEGs by querying the GeneCards database for name, fold change, p-value, location, and biological function. The gene highlighted in red (Fig. [85]4B), SKG1, was the most significant differential gene. We then localized the DEG SGK1 to the PI3K/SGK1/Foxo3 signaling pathway using GO and KEGG enrichment analyses (Fig. [86]4C-E). We subsequently validated these findings using RT-PCR, normalizing gene expression to that of β-actin, along with western blot and hippocampal tissue analyses (Fig. [87]4F-H). All assays consistently revealed a significant reduction in the gene and protein expression of SGK1 following noise exposure(Figure [88]S2E). Fig. 4. Fig. 4 [89]Open in a new tab Noise exposure induces SGK1 downregulation in hippocampal tissues. (A) Volcano plot of differentially expressed genes (DEGs) between the control and noise-exposed groups. Red, blue, and gray dots represent upregulated, downregulated, and non-differentially expressed genes, respectively (p < 0.05,|log[2]FC|>1.0). (B) Sankey & dot plot suggests that the differential gene SGK1 was enriched in the PI3K/Akt signaling pathway. (C) Protein-protein interaction (PPI) network of intersecting DEGs. (D) Gene expression in the adherens junction pathway was plotted using PATHVIEW. Red and green represent upregulated and downregulated genes, respectively, in the noise-exposed group. (E) DEGs and Kyoto Encyclopedia of Genomes (KEGG) pathway enrichment analyses of the control and noise-exposed groups. F-G. SGK1 mRNA expression in hippocampal tissues (ΔΔct relative quantitative) and representative western blot bands of SGK1 in hippocampal tissues. n = 3. Values are expressed as means ± SEM. *p < 0.05, **p < 0.01. (H). Linear regression was used to assess the correlation between the levels of SGK1 mRNA (transcriptome data) and SGK1 protein (western blot data) SGK1-mediated intracellular PI3K/SGK1/Foxo3 signaling pathway leads to hippocampal neuronal damage and apoptosis after around-the-clock noise exposure Protein processing in the SGK1 pathway was enriched using the KEGG analysis based on RNA sequencing data. There was a significant increase in the protein expression of p-PI3K/PI3K after noise exposure (Fig. [90]5A-I). The susceptibility of hippocampal neurons to SGK1 is noteworthy, and KEGG pathway enrichment analyses suggested that the apoptotic pathway may play an important role in cognitive impairment after noise exposure. Furthermore, the fluorescence intensity of SGK1 in the hippocampal tissues of rats exposed to noise stemming significantly decreased, whereas the fluorescence intensity of its negative regulator FOXO3 significantly increased (Fig. [91]5J). Fig. 5. [92]Fig. 5 [93]Open in a new tab SGK1-mediated intracellular pathological change contributes to apoptosis following noise exposure. (A)-(I). Representative western blot bands of p-PI3K, PU3K, p-PDK1, PDK1, P-Akt, Akt, SGK1, p-Foxo3, Foxo3, Bim, Bcl-6, and FasL in hippocampal tissues. (J). Immunofluorescence staining was used to determine changes in SGK1 and Foxo3 in hippocampal CA3 and CA1 regions. (K). Immunofluorescence staining was used to determine changes in SGK1 and Foxo3 in hippocampal CA1 region. Scale bar = 100 μm. Values are expressed as means ± SEM. n = 3,*p < 0.05, **p < 0.01 Discussion The present study revealed the critical role of SGK1 in around-the-clock noise-induced cognitive dysfunction using an in vivo model. We demonstrated that prolonged noise exposure leads to significant neuronal apoptosis in the hippocampus, accompanied by the accumulation of markers of cognitive damage. These results suggest a potential pathway by which environmental noise contributes to cognitive impairment, warranting further exploration of the underlying molecular mechanisms. The occupational noise exposure limit is a time-weighted average of 85 dBA for 8 h per day. Noise is avoided for the remaining 16 h to ensure sufficient time to recover from the temporary auditory and non-auditory effects caused by noise exposure. However, operators engaged in special occupations such as long haul ship captains often perform long-term work tasks and are located in limited spaces such as ship cabins. Whether during work or rest time, they are inevitably exposed to complex noise environments such as power, machinery, and even weapons. Research has shown that the 24-hour equivalent sound level of noise radiated directly from the flight deck to adjacent areas and operating heavy equipment during the takeoff and landing operations of US Navy aircraft carriers is approximately 71 to 127 dB [[94]6]. Research has shown that the main health risk caused by long-term noise exposure in the long-term cabin operating environment of ships is chronic pathological damage caused by the sustained accumulation of multi system non auditory effects. Long term continuous noise exposure can lead to neurobehavioral dysfunction, ultimately affecting the ability of workers to perform cognitive related tasks [[95]27]. In this study, we confirmed that around-the-clock noise exposure induced abnormalities in spatial learning and memory, evidenced by reduced autonomous exploration and diminished spatial search abilities for platforms in MWM test, were consistent with the results of previous studies [[96]3, [97]4, [98]28]. Importantly, a recent study indicates that noise exposure can cause structural and functional abnormalities in both the auditory cortex and hippocampus, with the hippocampus potentially being more vulnerable to environmental noise than the auditory cortex [[99]28]. Thus, it is reasonable to postulate that noise-induced working memory impairment may also be hippocampal dependent. The hippocampus and prefrontal cortex play important roles in spatial learning and memory and are also involved in integrating physiological processes such as cognition and emotional information [[100]29]. In the MWM test, spatial navigation is a hippocampus dependent memory, and the rats need to integrate visual/spatial cues from the environment (such as wall markings and light positions) to form spatial memory of the location of the escape platform. This process is highly dependent on the CA1 and CA3 regions of the hippocampus. Our results demonstrated that continuous noise exposure worsened not only cognitive impairment in rats, but also revealed histopathological changes. These included the deposition of Aβ plaques in the hippocampal region, cytoarchitectural damage, and a marked increase in the expression of apoptosis-related proteins caspase-3, caspase-12, and Bax, suggesting that neuronal apoptosis occurred in the CA1 and CA3 regions of hippocampus. Specifically, the upregulation of pro-apoptotic proteins, such as Bax, FasL, and TRAIL, as well as the downregulation of the anti-apoptotic protein Bcl-2, suggests that hippocampal neurons have shifted to a pro-apoptotic state [[101]18, [102]27, [103]28]. This shift is particularly concerning, as it indicates that prolonged noise exposure may create a neurotoxic environment, leading to neuronal loss and thus exacerbating cognitive deficits. In the present study, we used transcriptome sequencing to screen and identify the SKG1 gene with the most significant hippocampal changes after noise exposure, and then localized the DEG SGK1 to the PI3K/SGK1/Foxo3 signaling pathway using GO and KEGG enrichment analyses. SGK1 is widely expressed in humans and is involved in the regulation of various processes, such as apoptosis [[104]30–[105]32], DNA damage, signal transduction, and ion transport across membranes [[106]33]. Genes encoding protein kinases (SGK1) and transcription factors (FOXO3) are dysregulated in AD, and their interactions play a role in regulating cell proliferation and cell death [[107]34]. The reduction in SGK1 expression and its corresponding protein levels observed in the hippocampus after exposure to around-the-clock noise suggests that this kinase is crucial in mediating neuronal health and cognitive function. Dysregulation of SGK1 may lead to the activation of the PI3K/SGK1/Foxo3 signaling pathway, which is implicated in the regulation of apoptosis. These results suggest that SGK1, a key molecule associated with neuronal apoptosis, may play a critical role in the subsequent cognitive impairment induced by all-weather noise exposure, which may have important etiological implications. This study highlights the deleterious effects of chronic noise exposure on cognitive health and provides insight into the underlying molecular mechanisms, laying the foundation for further exploration of therapeutic interventions. Furthermore, activation of the PI3K/SGK1/Foxo3 pathway in response to noise exposure highlights the potential for environmental stressors to influence intracellular signaling cascades and neuronal survival. The interaction between SGK1 and Foxo3 is particularly noteworthy, because Foxo3 is a transcription factor involved in various physiological and pathological processes, including oxidative stress, proliferation, apoptosis, immunity, and differentiation [[108]35]. Foxo3 is specifically phosphorylated by SGK1, leading to its exclusion from the nucleus and thus inhibiting its ability to function as a transcription factor [[109]36]. Moreover, prolonged activation of this pathway may lead to a deleterious feedback loop, whereby increased apoptosis further impairs cognitive function and neuronal integrity. Our study found that the expression of SGK1, which encodes serum/glucocorticoid-regulated kinase 1, was significantly reduced in the hippocampal tissues of noise-exposed subjects. This dysregulation inhibited the PI3K/SGK1/Foxo3 signaling pathway, leading to the upregulation of apoptotic markers such as Bcl-2, Bax, Fasl, and TRAIL. These findings highlight the deleterious effects of chronic noise exposure on cognitive function and shed light on potential molecular pathways that could be targeted for therapeutic intervention, thus highlighting the important contribution of this study to understanding the interaction between environmental stressors and neurodegenerative processes. Although this study provides valuable insights into the mechanisms by which around-the-clock noise exposure leads to cognitive impairment and neuronal apoptosis, it has a few limitations. First, while using an animal model is essential for understanding the underlying biological processes, it may not fully replicate the complexity of human cognitive function and the multifactorial nature of noise-induced cognitive decline in occupational settings. Additionally, the duration and intensity of noise exposure in the experimental design may not accurately reflect the actual conditions experienced by workers, which may limit the generalizability of the findings. Future studies should address these limitations by employing longitudinal designs, varying noise exposure parameters, and exploring additional molecular pathways to improve the translational relevance of our findings. Conclusion Our findings demonstrate that exposure to around-the-clock noise environments leads to significant cognitive decline and neuronal damage, primarily through dysregulation of the SGK1 gene and activation of the PI3K/SGK1/Foxo3 signaling pathway. The observed reduction in SGK1 expression was associated with elevated levels of apoptotic markers, suggesting a mechanistic link between chronic noise exposure and hippocampal neuronal apoptosis (Fig. [110]6). This study not only elucidates the pathological process of impaired cognitive function in noise-exposed individuals but also highlights the potential for targeting the PI3K/SGK1/Foxo3 pathway as a therapeutic strategy to mitigate the detrimental effects of environmental stressors on cognitive health. Future studies should focus on elucidating the molecular interactions in this pathway and explore possible interventions to ameliorate cognitive deficits associated with chronic noise exposure. Furthermore, targeting the activation of SGK1 is a promising strategy that may provide a new therapeutic avenue to address cognitive decline following noise exposure. Fig. 6. [111]Fig. 6 [112]Open in a new tab Schematic diagram showing the possible mechanism of noise-induced cognitive decline. Noise inhibits the activation of the PI3K/SGK1/Foxo3 signaling pathway by downregulating SGK1 expression, leading to apoptosis, neuronal damage, and cognitive impairment Electronic supplementary material Below is the link to the electronic supplementary material. [113]Supplementary Material 1^ (15.4MB, docx) Acknowledgements