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PI3K/Akt pathway and neuroinflammation in sepsis-associated encephalopathy

  • Yang Guo and Yonghao Yu EMAIL logo
Published/Copyright: August 7, 2025
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Open Medicine
From the journal Open Medicine Volume 20 Issue 1

Abstract

Background

Sepsis-associated encephalopathy (SAE) is a complex neurological complication of sepsis involving activation of microglia in the central nervous system (CNS), blood–brain barrier (BBB) dysfunction, neurotransmitter dysfunction, impaired brain metabolism, and mitochondrial dysfunction. Neuroinflammation is a critical component of the pathogenesis. The phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, as a key intracellular signaling pathway, plays a crucial role in regulating neuroinflammation, maintaining the integrity of the BBB, and promoting neuronal cell survival.

Objective

This review aims to summarize the role of the PI3K/Akt pathway in SAE-associated neuroinflammation and highlights potential therapeutic targets and strategies for its management.

Methods

We systematically reviewed recent basic and clinical studies on PI3K/Akt signaling pathway in neuroinflammation associated with SAE, as well as the development of pathway-specific agonists and inhibitors.

Results

The PI3K/Akt pathway serves as a crucial intracellular signaling axis involved in the regulation of neuroinflammatory processes. Accumulating evidence indicates that targeted modulation of this pathway may alleviate neuroinflammation associated with SAE and enhance neurological recovery.

Conclusion

Targeting the PI3K/Akt pathway represents a promising therapeutic approach for SAE. Advances in the development of specific agonists and inhibitors provide new opportunities for clinical translation and drug discovery in neuroinflammatory conditions.

Keywords: sepsis-associated encephalopathy; PI3K/Akt pathway; neuroinflammation; blood–brain barrier; cognitive dysfunction

1 Introduction

Sepsis is a systemic inflammatory response syndrome (SIRS) caused by infection, characterized by dysregulation of the body’s immune response to infection. It is one of the key causes of death in critically ill patients in the intensive care unit [1]. Among these, sepsis-associated encephalopathy (SAE) is one of the most common complications of sepsis, with an incidence rate as high as 70% [2], which significantly increases the morbidity and mortality rate and diminishes the quality of life of the patients [3,4]. The pathogenesis of SAE is complex and multifactorial, with contributing key factors including activation of microglia in the central nervous system (CNS), blood–brain barrier (BBB) dysfunction, brain edema, neurotransmitter dysfunction, impaired brain metabolism, and mitochondrial dysfunction [5–8]. Additional mechanisms, such as the accumulation of amyloid-β and tau proteins, activation of the complement system, and direct neuronal injury, may also contribute to the development of SAE [9]. Overall, SAE results from the synergistic effects of multiple factors, rather than a single cause. Among these, neuroinflammation has been shown to play a crucial role throughout the SAE process and is closely associated with prognosis.

Neuroinflammation is an immune response activated by microglia and astrocytes in the CNS, usually occurring in response to CNS injury, infection, toxin stimulation, or autoimmunity [9]. Systemic inflammation induced by sepsis is mediated by the excessive release of proinflammatory cytokines – such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) – which increases the permeability of the BBB, thereby facilitating inflammatory factors to enter the brain and trigger an inflammatory response in the CNS. The sustained inflammatory response disrupts the BBB and facilitates the infiltration of peripheral immune cells. This exacerbates CNS injury, leading to neuronal damage [10,11], demyelination [12], impaired regeneration [13], and synaptic dysfunction.

Among the numerous molecular pathways implicated in neuroinflammation, the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway has been extensively studied for its involvement in various physiological processes within the CNS, including cell survival, autophagy, neurogenesis, neuronal proliferation and differentiation, synaptic plasticity, anti-apoptosis, anti-oxidative stress, and neural repair [9,14]. Recently, several studies have confirmed that this pathway is closely related to the development of neurological diseases and plays an important role in modulating various pathological changes [15–17].

Based on the roles of neuroinflammation and PI3K/Akt pathway activation in the pathogenesis of SAE, this article aims to elucidate their specific roles and interrelationships in SAE development. The following sections will comprehensively describe the neuroinflammation triggered by sepsis, the underlying mechanisms of the PI3K/Akt pathway, its role in SAE, and the potential treatment of SAE through targeting the PI3K/Akt pathway.

2 Sepsis-induced neuroinflammation

The presence of neuroinflammation in SAE has been clearly demonstrated [18,19]. Autopsy studies of patients who died from sepsis revealed significantly increased expression of markers associated with acute neuroinflammation, suggesting that neuroinflammation may play a critical role in the progression of SAE [20]. While infection does not occur directly in the brain, peripheral inflammatory signals can trigger widespread neuroinflammation through both neuronal and humoral pathways [21]. Neuroinflammation is initiated by multiple biological mechanisms, including immune responses, oxidative stress, the release of inflammatory mediators, and damage to the BBB. Although neuroinflammation can initially have a protective effect, prolonged or excessive inflammation can result in neural tissue damage.

Neuroinflammatory responses can be classified into two categories: secondary inflammatory responses induced by peripheral immune cells and primary inflammatory responses triggered by resident immune cells. Initially, during sepsis, pathogens or their associated toxins – such as lipopolysaccharide (LPS) – stimulate the host immune system, leading to an exaggerated inflammatory response and the subsequent development of SIRS. These peripheral inflammatory signals affect the CNS through two main pathways: humoral and neuronal. Through the humoral pathway, elevated circulating pro-inflammatory factors (TNF-α, IL-1β, and IL-6) enter the brain via the disrupted BBB and directly activate CNS inflammation. In a septic environment, the intense secretion of inflammatory factors and chemokines recruits peripheral immune cells, such as neutrophils and macrophages, to the brain, thereby exacerbating neuronal damage [22,23]. Neuroinflammation can also be amplified through neurotransmission, with the vagus nerve upregulating pro-inflammatory gene expression by transmitting signals to the nucleus tractus solitarius of the medulla oblongata [24]. This central-peripheral inflammation cascade amplifies the inflammatory response. In sepsis, microglia become hyperactivated, releasing large amounts of pro-inflammatory cytokines (TNF-α, IL-1β) and chemokines (MCP-1). Overactivated microglia induce apoptosis and synaptic damage in neurons, stimulate reactive oxygen species (ROS) production [25], and further trigger oxidative stress and inflammatory cascades. Astrocytes are also activated [26], and synergize with microglia to exacerbate the inflammatory response. This includes breaking down matrix components in the BBB, leading to barrier disruption, and secreting large quantities of inflammatory factors (IL-6), which promote the spread of inflammation. Cytokines and chemokines also disrupt the integrity of the BBB by affecting the expression of tight junction proteins (Claudin, Occludin) [22,23,27]. The sepsis-induced immune response produces an abundance of pro-inflammatory factors (TNF-α, IL-1β), which bind to specific receptors and activate apoptotic signaling pathways such as Fas and Caspase [28,29]. This activation ultimately leads to neuronal and glial cell death, causing further damage to the nervous system. Additionally, activated inflammatory mediators and immune cells generate ROS and reactive nitrogen species, leading to increased oxidative damage [30,31]. These free radicals damage cell membranes, proteins, and DNA, which further contribute to neuronal dysfunction, apoptosis, and long-term neurological impairment. Sepsis-induced oxidative stress also disrupts mitochondrial function, compromising the cellular energy supply. Mitochondrial damage exacerbates neuronal apoptosis and creates a vicious cycle by releasing cytokines and activating neuroinflammatory pathways [32].

3 PI3K/Akt pathway and its role in brain tissue

The PI3K/Akt signaling pathway consists of two main components: phosphatidylinositol 3 (PI3K) and its downstream serine/threonine protein kinase B (PKB, also known as Akt). PI3K is a class of intracellular lipid kinases, classified into types I, II, or III based on substrate specificity and sequence homology [33,34]. Akt is a proto-oncogene product that, upon activation, modulates a variety of downstream signaling molecules, including mammalian target of rapamycin (mTOR) [35] and glycogen synthase kinase-3 (GSK-3) [36], among others.

The PI3K/Akt signaling pathway is a central intracellular regulatory network involved in diverse biological processes, including cell survival, proliferation, metabolism, protein synthesis, immune regulation, and stress responses. By promoting proliferation, inhibiting apoptosis, and enhancing cell survival, this pathway plays a critical role in tumorigenesis and has emerged as a prominent target for cancer therapy [37–39]. Akt, a key effector of the PI3K/Akt pathway, regulates glucose and lipid metabolism, as well as cell differentiation and growth [40], and holds therapeutic potential for diabetes and metabolic disorders. The PI3K/Akt/mTOR pathway also plays a critical role in bone and joint diseases, such as osteoarthritis [41], and in erythroid hematopoiesis [40], suggesting its potential as a novel therapeutic target. In neurological disorders, the PI3K/Akt pathway regulates neuronal survival, mitigates inflammation, preserves BBB integrity, and exerts neuroprotective effects in conditions such as Alzheimer’s and Parkinson’s diseases [42,43]. Thus, the PI3K/Akt pathway holds broad clinical potential across various diseases, including cancer, metabolic disorders, neurological conditions, and osteoarticular diseases.

In normal brain tissues, the PI3K/Akt signaling pathway plays a crucial role in neuronal survival, synaptic plasticity, energy metabolism, BBB integrity, and neurodevelopment [44]. The activation of this pathway depends on upstream ligands such as derived brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1), and mediates multiple regulatory effects on neuronal anti-apoptosis, resistance to oxidative stress, synaptic plasticity, and energy metabolism through downstream targets including mTOR, GSK-3β, and cAMP response element-binding protein 2 [45]. For example, Akt inhibits the mitochondrial apoptotic pathway by phosphorylating pro-apoptotic proteins such as BAD and Caspase-9, thereby preventing premature neuronal apoptosis and contributing to the maintenance of the functional integrity of brain tissue [46]. Akt exerts antioxidant effects by activating the Nrf2 pathway and scavenging ROS [47]. It also activates mTOR-dependent protein synthesis to support dendritic spine formation and long-term potentiation (LTP) [47], and promotes the membrane translocation of the glucose transporter GLUT4 to enhance neuronal glucose uptake. In addition, Akt plays a key role in stabilizing the intracerebral microenvironment by maintaining the expression of endothelial tight junction proteins, such as Zonula Cccludens-1 (ZO-1), at the BBB [48].

However, in the pathological state of SAE, the systemic inflammatory response and oxidative stress lead to inhibition of the PI3K/Akt signaling pathway. Proinflammatory cytokines, such as TNF-α and IL-1β, released during sepsis indirectly suppress the activity of the PI3K catalytic subunit p110 via activation of the nuclear factor kappa B (NF-κB) pathway [25]. Simultaneously, excessive ROS promote the conversion of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) to phosphatidylinositol 4,5-bisphosphate (PIP2) by activating the lipid phosphatase PTEN, a negative regulator of PI3K, thereby impairing Akt membrane localization and phosphorylation [49]. Mitochondrial dysfunction further exacerbates energy metabolism disorders and reduces the efficiency of Akt activation [25]. Akt inactivation results in the dephosphorylation of BAD, which in turn activates Bax/Bak-mediated mitochondrial cytochrome c release and triggers the caspase cascade, ultimately enhancing neuronal apoptosis. Additionally, GSK-3β disinhibition leads to Tau protein hyperphosphorylation, promoting the formation of neurofibrillary tangles and downregulating the expression of synapse-associated proteins such as PSD-95, contributing to synaptic damage [50]. Decreased Akt activity in endothelial cells also compromises tight junction integrity, aggravating brain edema and neuroinflammation.

In summary, the PI3K/Akt pathway plays a critical role in maintaining CNS homeostasis under normal conditions. However, in SAE, its expression and activity are markedly altered, resulting in the loss of its original protective functions and, in some cases, contributing to disease progression. Comparing the dynamic changes of this pathway between physiological and pathological states may help elucidate its role in SAE pathogenesis and provide a theoretical foundation for targeted therapeutic interventions. (Figure 1).

Figure 1 Differences in PI3K/Akt pathway in normal brain tissue and SAE conditions. ROS: reactive oxygen species.
Figure 1

Differences in PI3K/Akt pathway in normal brain tissue and SAE conditions. ROS: reactive oxygen species.

4 PI3K/Akt pathway and neuroinflammation in SAE

As discussed previously, sepsis-induced neuroinflammation is a core pathogenic mechanism of SAE. Within the pathophysiological framework of SAE, the PI3K/Akt pathway plays a dual regulatory role in both CNS injury and neuroprotection. It does so by modulating the expression of neuroinflammatory factors, regulating microglial activation, maintaining the integrity of the BBB, and controlling neuronal apoptosis. The PI3K/Akt pathway is a classical signaling cascade that regulates neuronal survival and neurogenesis, making it a crucial player in the progression and potential treatment of SAE [40,51]. In the CLP mouse model, protein expression levels of PI3K and Akt in hippocampal tissues were significantly decreased [52–54], whereas activation of the PI3K/Akt pathway attenuated SAE-related damage [52–57].

4.1 Regulation of inflammatory factors

The PI3K/Akt pathway suppresses the excessive release of pro-inflammatory cytokines during sepsis through multiple mechanisms. First, it initiates a negative feedback regulatory loop that significantly reduces the overexpression and secretion of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6 [58–60]. Second, the pathway upregulates the expression of anti-inflammatory mediators, such as IL-10, which subsequently inhibits pro-inflammatory cytokine production via paracrine signaling [58]. Additionally, the PI3K/Akt pathway inhibits the activation and nuclear translocation of NF-κB, further modulating inflammation [61]. It also contributes to the regulation of the Th1/Th2 cytokine balance [62], thereby attenuating the inflammatory cascade. Clinical studies have confirmed that pharmacological agents like dexmedetomidine [63] and metformin [64] can activate the PI3K/Akt pathway, inhibiting pro-inflammatory cytokine release and improving sepsis-associated brain and lung injury.

4.2 Regulation of microglia polarization

The PI3K/Akt signaling pathway plays a crucial role in regulating microglia polarization. It modulates microglial M1/M2 polarization by influencing multiple signaling pathways [65], including NF-κB [66] and chemokine receptor CXCR7 [67], which promote the transformation of microglia to the M2 phenotype and enhance their anti-inflammatory properties. M2-polarized microglia secrete anti-inflammatory cytokines, such as IL-10 and TGF-β [68], thereby reducing the neuroinflammatory response. Agents like tretinoin and curcumin have been demonstrated to inhibit the activation of pro-inflammatory M1 microglia while promoting the anti-inflammatory properties of M2 microglia, presumably via activation of the PI3K/Akt pathway [69]. Furthermore, the PI3K/Akt pathway indirectly regulates microglial inflammation by modulating the neuron-derived BDNF-PI3K/Akt signaling axis [70,71]. Akt increases the secretion of BDNF from neurons by enhancing vesicular transport, which in turn strengthens the inhibitory effect of neurons on microglial inflammation. Compounds like pineoside [72] and paeoniflorin [72] regulate the BDNF-PI3K/Akt axis, achieving a balanced regulation of microglia M1/M2 polarization and alleviating neuroinflammatory disorders such as SAE.

4.3 Maintenance of BBB integrity

The PI3K/Akt pathway plays a crucial role in maintaining the integrity of the BBB. Akt regulates the expression of tight junction proteins, such as Claudin, Occludin, and ZO-1, through the activation of the PI3K/Akt pathway, thereby preserving BBB structural integrity [73,74]. Chen et al. [75] demonstrated in an in vitro BBB model that activation of the PI3K/Akt pathway enhances the transcription and translation of tight junction proteins, resulting in decreased permeability of endothelial cell monolayers. Wang et al. [76] found that in a murine model of sepsis treatment with a PI3K-selective agonist significantly increased the expression of tight junction proteins in brain microvascular endothelial cells. Additionally, the PI3K/Akt pathway inhibits the TNF-α- and IL-1β-induced expression of matrix metalloproteinases, thereby reducing extracellular matrix degradation and protecting the BBB structure [77]. Zhi et al. [78] observed that selective PI3K agonist treatment significantly reduced levels of S100β and neuron-specific enolase in the cerebrospinal fluid of sepsis patients, along with other markers of BBB damage, and improved neurocognitive function scores. Gong et al. [79] reported that combined administration of a PI3K agonist and an anti-inflammatory agent significantly reduced the morbidity and mortality of patients with SAE, and the levels of tight junction protein degradation products, such as Occludin and Claudin-5 fragments, were notably lower in the peripheral blood of treated patients. This suggests that the combination regimen may exert neuroprotective effects by preserving BBB integrity.

4.4 Regulation of neuronal apoptosis

Neuronal apoptosis is a key pathological feature in sepsis-induced neuroinflammation, with its regulatory mechanisms linked to the PI3K/Akt pathway. First, the PI3K/Akt pathway inhibits neuronal apoptosis by regulating several downstream effector molecules. Activated Akt effectively blocks Bad-induced apoptosis by phosphorylating Bad at the Ser136 site, preventing its binding to Bcl-2. Additionally, the pathway upregulates the nuclear translocation of the antioxidant-related transcription factor Nrf2, which increases the expression of superoxide dismutase and catalase, thereby reducing oxidative stress-induced neuronal injury. Puerarin has been shown to reduce neuronal apoptosis by inhibiting oxidative stress through the PI3K/Akt/Nrf2 pathway [80]. Furthermore, the PI3K/Akt pathway promotes neural repair and regeneration. Akt-mTOR signaling enhances myelin sheath growth and stability during development by driving cap-dependent translation to facilitate myelin formation [81]. It has also been demonstrated that resveratrol can activate PI3K/Akt signaling to promote axonal regeneration and neurological recovery. Additionally, the PI3K/Akt pathway may play a role in regulating synaptic plasticity by modulating the reorganization of post-synaptic proteins, such as PSD-95 [82], and influences synaptic transmission efficiency as well as LTP [83]. Moreover, novel PI3K agonists have shown promising neuroprotective effects in animal models, providing new intervention targets for the treatment of SAE [84].

4.5 Discovery of new molecules

In recent years, several novel molecules have been identified as regulators of the PI3K/Akt pathway, with significant effects on the development and progression of SAE. Protein kinase N2 (PKN2), in particular, exerts a broad range of regulatory effects on the PI3K/Akt signaling pathway through mechanisms such as direct phosphorylation, modulation of membrane localization, and catalytic activity. PKN2 can directly phosphorylate the p85 regulatory subunit of PI3K [85], inducing a conformational change that alters its interactions with other signaling molecules. Furthermore, PKN2 affects the membrane localization of PI3K, thereby modulating its enzymatic activity [85]. Wang et al. [86] demonstrated that PKN2 overexpression activated the mTOR pathway in PC12 cells, reducing H2O2-induced oxidative damage and apoptosis. Additionally, PKN2 modulates Akt activity by phosphorylating its Ser473 site [87], a key step in regulating the function of Akt within the PI3K/Akt pathway. By phosphorylating Akt at this critical site, PKN2 influences the activity and substrate specificity of Akt, thereby affecting downstream signaling processes. In addition, PKN2 may play a role in regulating the integrity of the BBB [88]. Bai et al. [89] found that H2 alleviates septic brain injury by activating PKN2 phosphorylation, which is associated with the PI3K pathway. While PKN2 exerts a broad range of regulatory effects on the PI3K/Akt signaling pathway, there are currently fewer studies focusing on its role in septic encephalopathy. This presents an opportunity for future, more in-depth research. PTEN, as a negative regulator of the PI3K/Akt pathway, inhibits AKT activation by dephosphorylating PIP3 and converting it to PIP2 [90]. This action helps maintain normal neuronal function and survival, protecting against neuronal injury caused by dysregulated signaling. Furthermore, the signaling between PTEN-induced kinase 1 (PINK1) and the Parkin pathway is crucial in SAE. High expression of PINK1 can activate mitochondrial autophagy through up-regulation of Parkin, which reduces inflammatory responses, preventing neuroinflammation and alleviating cognitive impairments in SAE mice. In the absence of PINK1, there is a suppression of Ca2+ transients in the hippocampus, leading to elevated intracellular Ca2+ levels, which exacerbate sepsis-induced cognitive dysfunction in mice, highlighting the vital role of PINK1 in maintaining neuronal stability [91]. Girdin can inhibit the production of pro-inflammatory cytokines, promote neuronal survival, and prevent apoptosis by regulating the activation of the PI3K/Akt pathway, thereby alleviating neuroinflammation [92,93]. Phosphorylated Girdin enhances the activity of intracellular anti-apoptotic factors, such as Bcl-2 and mTOR, which reduce programmed cell death [94]. Additionally, Girdin regulates microglial activation, as overactivation of microglia exacerbates the neuroinflammatory response. Rheb (Ras homolog enriched in brain), a small GTP-binding protein, plays a key role in the PI3K/Akt/mTOR signaling pathway by directly activating mTOR, which is crucial for neuroprotection. In an LPS-induced neuroinflammation model, upregulation of Rheb was linked to astrocyte proliferation and neuronal apoptosis [95]. The Rheb-mTOR signaling pathway contributes to neuroinflammation-induced astrocyte activation and neuronal apoptosis through cell cycle activation [96]. Moreover, specific overexpression of Rheb in retinal ganglion cells significantly reduced cell death and effectively induced axonal regeneration [97], suggesting that Rheb promotes neural repair, potentially alleviating sepsis-induced neuroinflammation. Additionally, BAG3 is involved in regulating Akt downstream targets like mTORC1, affecting cellular autophagy processes. BAG3 forms a complex with CHIP (C-terminus of Hsc70 interacting protein) [98], which facilitates the ubiquitination and degradation of key inhibitors negatively regulating PI3K/Akt signaling, such as phosphatase and Tensin homolog deleted on chromosome 10 (PTEN), thereby positively regulating this pathway. Bcl-2-associated athanogene 3 (BAG3) also plays a protective role in sepsis-induced acute kidney injury (AKI), and studies have shown that sevelamer sodium can attenuate AKI in a rat sepsis model through inhibition of the PI3K/Akt pathway, with BAG3 involved in this protective mechanism. Although there are currently fewer studies directly examining these molecules in SAE, they play critical roles in the PI3K/Akt signaling pathway, which is integral to SAE pathogenesis. Future research should focus on how these molecules specifically contribute to SAE and whether they can be targeted for effective therapeutic interventions, potentially offering more effective treatments for patients with SAE (Figure 2).

Figure 2 Inflammatory signaling regulates SAE through the PI3K/Akt pathway. PAMPs: pathogen-associated molecular patterns; DAMPS: damage-associated molecular patterns; LTA: lipoteichoic acid; NTS: nucleus tractus solitarius; BBB: blood–brain barrier.
Figure 2

Inflammatory signaling regulates SAE through the PI3K/Akt pathway. PAMPs: pathogen-associated molecular patterns; DAMPS: damage-associated molecular patterns; LTA: lipoteichoic acid; NTS: nucleus tractus solitarius; BBB: blood–brain barrier.

5 Therapeutic potential of PI3K/Akt pathway modulators

IGF-1 attenuates the inflammatory response and ameliorates SAE by activating the PI3K/Akt pathway. Treatment with recombinant human IGF-1 significantly reduced serum levels of IL-1β, TNF-α, and IL-6 in patients with SAE, while also improving the Glasgow Coma Score (GCS), strengthening BBB integrity, reducing neuroinflammation, and enhancing cognitive function [99,100]. BDNF activates the PI3K/Akt signaling pathway through the TrkB receptor, upregulates the expression of the anti-apoptotic protein Bcl-2, and promotes the expression of synaptic plasticity-associated proteins (PSD95) [101,102]. BDNF has been shown to significantly ameliorate memory deficits in a mouse model of sepsis and reduce the expression of pro-inflammatory cytokines in the CNS. Several studies have shown that various naturally active compounds exert neuroprotective effects by modulating the PI3K/Akt signaling pathway. Curcumin significantly increased the level of phosphorylated Akt in neurons (the p-Akt/Akt ratio increased 2.1-fold), promoting the nuclear translocation of Nrf2 and enhancing cellular resistance to oxidative stress [103]. Resveratrol significantly reduced the volume of cerebral infarcts and neurological damage scores in cerebral ischemia/reperfusion rats, significantly lowering levels of myeloperoxidase, TNF-α, and upregulating p-Akt expression. The use of Akt inhibitors blocked the effects of resveratrol. Resveratrol was also shown to reduce neuronal apoptosis, as evidenced by an increase in the Bcl-2/Bax ratio and a decrease in the number of TUNEL-positive apoptotic cells [104]. Additionally, quercetin and rhodiola rosea glycosides synergistically activate PI3K/Akt downstream targets, significantly reducing pro-inflammatory factors and improving cognitive function [105,106]. Oleanolic acid [107] and dihydromyricetin (DHM) [108] inhibit oxidative stress through activation of the PI3K/Akt pathway, thereby exerting neuroprotective effects. Based on their role in other neuroinflammatory diseases, these natural compounds may have important therapeutic potential in SAE. In cases of overactivated PI3K/Akt signaling, the PI3K-selective inhibitor LY294002 exerts a bidirectional modulatory effect, reducing inflammatory responses and neurotoxicity [104,109]. However, the targets of PI3K inhibitors need to be carefully selected to avoid inhibiting neuroprotective effects.

Several PI3K inhibitors have been developed for tumor therapy, such as PI-103, BKM120, and GDC-0941 [110,111]. These inhibitors block tumor cell proliferation and survival by targeting key nodes of the PI3K/Akt pathway, including PI3K, Akt, and mTOR. Some PI3K inhibitors have been approved for the treatment of specific hematologic malignancies. For example, Linperlisib, the first highly selective PI3Kδ inhibitor marketed in China, has been approved for the treatment of relapsed and/or refractory follicular lymphoma (FL), demonstrating significant clinical efficacy and good tolerability [112]. In addition, Duvelisib [113], a dual PI3Kδ and PI3Kγ inhibitor, has also been approved by the FDA for the treatment of adult patients with relapsed/refractory chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and FL who have received at least two prior therapies. Although these drugs have shown effectiveness in treating specific types of hematologic malignancies, their potential application in neuroinflammatory and neurological disorders requires further research and exploration. Although most compounds targeting the PI3K/Akt pathway – such as estrogen [114], resveratrol, curcumin [115], GDC-0941, duvelisib, and leniolisib [112] – have already entered clinical trials for other diseases (oncology, metabolic disorders, and neurodegenerative diseases), their clinical application in sepsis, especially SAE, remains largely unexplored or is still in its infancy. This suggests that, in the future, compounds with established clinical safety profiles could be prioritized for translational research in SAE, particularly through the use of animal models to verify their target specificity and neuroprotective efficacy (Table 1).

Table 1

Major research models, mechanisms, and key findings of PI3K/Akt pathway agonists and inhibitors associated with SAEs

Compound Mechanisms Model Key findings Ref.
Recombinant human IGF-1 Activates PI3K/Akt pathway to reduce inflammation C57BL/6 mice; sepsis induced by intratracheal instillation of P. aeruginosa (PA103 strain) Decrease in serum IL-1β, TNF-α, IL-6 levels; increase in GCS score; enhancement of BBB function; decrease in neuroinflammation and improvement in cognitive ability [99,100]
BDNF Activates the PI3K/Akt pathway via TrkB receptors SCID-Beige mice; NB xenograft model for metastasis Improvement of memory deficits and reduction of pro-inflammatory cytokines in CNS [101,102]
Estrogen Activates PI3k/Akt, upregulates Bcl-2, and downregulates Bax and Caspase-3,8 VSC4.1 motor neuron cells Antiapoptotic [116]
Curcumin Increases phosphorylated Akt (p-Akt) and promotes Nrf2 nuclear translocation C57BL/6 mice; LPS-induced sepsis model; HL-1 cardiomyocytes; LPS stimulation Enhanced antioxidant stress response and 2.1-fold increase in p-Akt/Akt ratio, promoting neuroprotection [103]
Resveratrol Increases p-Akt expression and inhibits oxidative stress SD rats; MCAO-induced cerebral I/R injury model Reduced cerebral infarct volume, improved neurologic scores, decreased MPO, TNF-α, increased p-Akt, and decreased apoptosis [117]
Quercetin Activates PI3K/Akt pathway, anti-inflammatory effects C57BL/6 mice; G. parasuis-induced encephalitis model; mouse brain endothelial cells; G. parasuis stimulation Significantly reduced inflammatory cytokines and improved cognitive function [105,106]
Oleanolic acid Activates PI3K/Akt pathway to inhibit oxidative stress and neuroinflammation Rats; methylmercury-induced ALS model Reduces oxidative stress and neuroinflammation [107]
DHM Activates the PI3K/Akt pathway to reduce oxidative stress C57BL/6 mice; MPTP-induced Parkinson’s disease model; MES23.5 cells; MPP⁺ stimulation Reduces oxidative stress and neuroinflammation and provides neuroprotection [108]
PI-103 series PI3K inhibitor targeting the PI3K/Akt/mTOR axis Human tumor xenograft models (glioblastoma, breast cancer, leukemia, prostate cancer, etc.) Inhibits tumor cell proliferation and survival by targeting the PI3K/Akt/mTOR pathway [110,111]
BKM120 series PI3K inhibitor targeting the PI3K/Akt pathway Human tumor xenograft models (glioblastoma, breast cancer, leukemia, prostate cancer, etc.) Inhibits tumor cell growth and survival by blocking PI3K/Akt signaling [110,111]
GDC-0941 PI3K inhibitor targeting the PI3K/Akt pathway Human tumor xenograft models (glioblastoma, breast cancer, leukemia, prostate cancer, etc.) Inhibits tumor growth, metastasis, and survival in preclinical models by blocking PI3K/Akt signaling [110,111]
Imperius Highly selective PI3Kδ inhibitor Refractory/relapsed FL Approved for FL treatment in China; demonstrated significant clinical efficacy and tolerability [112]
Duvelisib Dual PI3Kδ/PI3Kγ inhibitor Refractory CLL and FL FDA approved for the treatment of CLL, SLL, and FL; effective in patients with relapsed/refractory disease [113]
LY294002 PI3K inhibitor targeting the PI3K pathway Rat astrocyte; LPS-induced astrocyte culture model used Inhibits the PI3K/Akt pathway; shows bidirectional regulation in overactive pathways, reducing inflammation and neurotoxicity [104,109]

6 Conclusion

Neuroinflammation is a key contributor to the pathogenesis of SAE, leading to CNS injury and adversely affecting cognitive function and patient survival. The underlying mechanisms primarily involve the activation of microglia and astrocytes, the release of pro-inflammatory cytokines and chemokines, disruption of the BBB structure, increased oxidative stress, and mitochondrial dysfunction. Among the numerous signaling pathways implicated in SAE, the PI3K/Akt pathway has emerged as a central regulator. This pathway plays a pivotal role in modulating neuroinflammatory responses, preserving BBB integrity, and promoting neuronal survival. Several studies have demonstrated that activation of the PI3K/Akt pathway by specific compounds can attenuate inflammation and neuronal damage, thereby alleviating SAE-related symptoms. However, the majority of these findings remain at the preclinical stage, and no PI3K/Akt-targeted agents have yet demonstrated clinical efficacy in SAE treatment.

As mentioned above, the PI3K/Akt signaling pathway plays a key role in regulating neuroinflammation, apoptosis, and BBB function, and holds great promise for clinical application. Activation of this pathway can reduce brain tissue damage and improve cognitive function, making it applicable to a variety of neurological diseases, including SAE. In addition, the PI3K/Akt pathway is closely related to immune system homeostasis. Moderate activation of this pathway can inhibit excessive immune responses and reduce systemic inflammation, which is particularly important in SAE, a condition characterized by a pathological “inflammatory storm.” Currently, several drugs targeting this pathway have entered clinical trials for oncology and metabolic diseases and have demonstrated favorable safety profiles. As a potential therapeutic target, the PI3K/Akt pathway is expected to offer a novel intervention strategy for diseases such as SAE in the future.

Despite these advances, several critical knowledge gaps remain. The PI3K family comprises multiple isoforms – PI3Kα, PI3Kγ, and PI3Kδ – each with distinct cellular distribution and functions. For example, PI3Kγ, as a central driver of microglial inflammatory responses, promotes M1-type polarization through the activation of chemokine receptors (the CXCL12–CXCR4 axis), thereby inducing NLRP3 inflammasome activation and the infiltration of peripheral immune cells into the brain [118]. PI3Kα, on the one hand, maintains neuronal metabolism and anti-apoptotic functions via the Akt/mTOR pathway [119]; on the other hand, its overactivation may exacerbate mitochondrial autophagy disorders due to oxidative stress [120]. Current research on the roles of these isoforms in SAE is limited, fragmented, and lacks systematic comparison and precise localization. Moreover, most studies have been conducted in acute animal models or in vitro systems, and their clinical relevance and translational potential remain to be validated. Notably, the PI3K/Akt pathway is intricately linked with multiple other signaling cascades – including MAPK, JAK/STAT, NF-κB, mTOR, and NLRP3 – which can induce diverse, and sometimes opposing, biological outcomes. This complexity makes it challenging to predict the net effect of pathway activation or inhibition in the inflammatory milieu of SAE.

Future studies should aim to delineate the cell-type-specific and stage-specific roles of individual PI3K isoforms during SAE progression and evaluate their potential as therapeutic targets in terms of efficacy and safety. Additionally, integrating single-cell transcriptomics and multi-omics approaches may provide insights into the dynamic crosstalk between the PI3K/Akt pathway and other signaling networks. On this basis, the development of selective, brain-targeted PI3K modulators, and the investigation of combination therapies – such as anti-inflammatory agents paired with BBB-protective compounds – may accelerate the translation of preclinical findings into clinically viable interventions for SAE.

# Yang Guo is the first author.

Acknowledgments

We sincerely thank Dr. Beibei Dong, Dr. Yuanyuan Bai, and Dr. Xiuhu An for their meticulous guidance and valuable suggestions during the preparation of this review. We also appreciate the support and assistance provided by our team members in data collection and discussions. Additionally, we acknowledge the Department of Anesthesiology at Tianjin Medical University General Hospital for providing excellent research conditions and support for this study.

  1. Funding information: Authors state no funding involved.

  2. Author contributions: Both authors contributed to the conception, design, writing, and revision of the manuscript. Yang Guo was responsible for the conceptualization, literature review, drafting, and preparation of the initial manuscript. Yonghao Yu provided guidance on the study design, critically revised the manuscript, and oversaw the finalization process. The corresponding author had full access to all study data and took responsibility for the decision to submit the manuscript for publication. Both authors have read and approved the final version of the manuscript.

  3. Conflict of interest: Authors state no conflict of interest.

  4. Data availability statement: This review article does not contain any new experimental data. All data referenced are derived from previously published studies.

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Received: 2025-02-20
Revised: 2025-06-27
Accepted: 2025-06-27
Published Online: 2025-08-07

© 2025 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/med-2025-1248
Keywords for this article
sepsis-associated encephalopathy; PI3K/Akt pathway; neuroinflammation; blood–brain barrier; cognitive dysfunction
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. Network pharmacological analysis and in vitro testing of the rutin effects on triple-negative breast cancer
  3. Impact of diabetes on long-term survival in elderly liver cancer patients: A retrospective study
  4. Knockdown of CCNB1 alleviates high glucose-triggered trophoblast dysfunction during gestational diabetes via Wnt/β-catenin signaling pathway
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  8. CMSP exerts anti-tumor effects on small cell lung cancer cells by inducing mitochondrial dysfunction and ferroptosis
  9. Predictive value of plasma sB7-H3 and YKL-40 in pediatric refractory Mycoplasma pneumoniae pneumonia
  10. Antiangiogenic potential of Elaeagnus umbellata extracts and molecular docking study by targeting VEGFR-2 pathway
  11. Comparison of the effectiveness of nurse-led preoperative counseling and postoperative follow-up care vs standard care for patients with gastric cancer
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  13. Adhered macrophages as an additional marker of cardiomyocyte injury in biopsies of patients with dilated cardiomyopathy
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  17. Lysophosphatidic acid 2 alleviates deep vein thrombosis via protective endothelial barrier function
  18. Transcription factor A, mitochondrial promotes lymph node metastasis and lymphangiogenesis in epithelial ovarian carcinoma
  19. Serum PM20D1 levels are associated with nutritional status and inflammatory factors in gastric cancer patients undergoing early enteral nutrition
  20. Hydromorphone reduced the incidence of emergence agitation after adenotonsillectomy in children with obstructive sleep apnea: A randomized, double-blind study
  21. Vitamin D replacement therapy may regulate sleep habits in patients with restless leg syndrome
  22. The first-line antihypertensive nitrendipine potentiated the therapeutic effect of oxaliplatin by downregulating CACNA1D in colorectal cancer
  23. Health literacy and health-related quality of life: The mediating role of irrational happiness
  24. Modulatory effects of Lycium barbarum polysaccharide on bone cell dynamics in osteoporosis
  25. Mechanism research on inhibition of gastric cancer in vitro by the extract of Pinellia ternata based on network pharmacology and cellular metabolomics
  26. Examination of the causal role of immune cells in non-alcoholic fatty liver disease by a bidirectional Mendelian randomization study
  27. Clinical analysis of ten cases of HIV infection combined with acute leukemia
  28. Investigating the cardioprotective potential of quercetin against tacrolimus-induced cardiotoxicity in Wistar rats: A mechanistic insights
  29. Clinical observation of probiotics combined with mesalazine and Yiyi Baitouweng Decoction retention enema in treating mild-to-moderate ulcerative colitis
  30. Diagnostic value of ratio of blood inflammation to coagulation markers in periprosthetic joint infection
  31. Sex-specific associations of sex hormone binding globulin and risk of bladder cancer
  32. Core muscle strength and stability-oriented breathing training reduces inter-recti distance in postpartum women
  33. The ERAS nursing care strategy for patients undergoing transsphenoidal endoscopic pituitary tumor resection: A randomized blinded controlled trial
  34. The serum IL-17A levels in patients with traumatic bowel rupture post-surgery and its predictive value for patient prognosis
  35. Impact of Kolb’s experiential learning theory-based nursing on caregiver burden and psychological state of caregivers of dementia patients
  36. Analysis of serum NLR combined with intraoperative margin condition to predict the prognosis of cervical HSIL patients undergoing LEEP surgery
  37. Commiphora gileadensis ameliorate infertility and erectile dysfunction in diabetic male mice
  38. The correlation between epithelial–mesenchymal transition classification and MMP2 expression of circulating tumor cells and prognosis of advanced or metastatic nasopharyngeal carcinoma
  39. Tetrahydropalmatine improves mitochondrial function in vascular smooth muscle cells of atherosclerosis in vitro by inhibiting Ras homolog gene family A/Rho-associated protein kinase-1 signaling pathway
  40. A cross-sectional study: Relationship between serum oxidative stress levels and arteriovenous fistula maturation in maintenance dialysis patients
  41. A comparative analysis of the impact of repeated administration of flavan 3-ol on brown, subcutaneous, and visceral adipose tissue
  42. Identifying early screening factors for depression in middle-aged and older adults: A cohort study
  43. Perform tumor-specific survival analysis for Merkel cell carcinoma patients undergoing surgical resection based on the SEER database by constructing a nomogram chart
  44. Unveiling the role of CXCL10 in pancreatic cancer progression: A novel prognostic indicator
  45. High-dose preoperative intraperitoneal erythropoietin and intravenous methylprednisolone in acute traumatic spinal cord injuries following decompression surgeries
  46. RAB39B: A novel biomarker for acute myeloid leukemia identified via multi-omics and functional validation
  47. Impact of peripheral conditioning on reperfusion injury following primary percutaneous coronary intervention in diabetic and non-diabetic STEMI patients
  48. Clinical efficacy of azacitidine in the treatment of middle- and high-risk myelodysplastic syndrome in middle-aged and elderly patients: A retrospective study
  49. The effect of ambulatory blood pressure load on mitral regurgitation in continuous ambulatory peritoneal dialysis patients
  50. Expression and clinical significance of ITGA3 in breast cancer
  51. Single-nucleus RNA sequencing reveals ARHGAP28 expression of podocytes as a biomarker in human diabetic nephropathy
  52. rSIG combined with NLR in the prognostic assessment of patients with multiple injuries
  53. Toxic metals and metalloids in collagen supplements of fish and jellyfish origin: Risk assessment for daily intake
  54. Exploring causal relationship between 41 inflammatory cytokines and marginal zone lymphoma: A bidirectional Mendelian randomization study
  55. Gender beliefs and legitimization of dating violence in adolescents
  56. Effect of serum IL-6, CRP, and MMP-9 levels on the efficacy of modified preperitoneal Kugel repair in patients with inguinal hernia
  57. Effect of smoking and smoking cessation on hematological parameters in polycythemic patients
  58. Pathogen surveillance and risk factors for pulmonary infection in patients with lung cancer: A retrospective single-center study
  59. Necroptosis of hippocampal neurons in paclitaxel chemotherapy-induced cognitive impairment mediates microglial activation via TLR4/MyD88 signaling pathway
  60. Celastrol suppresses neovascularization in rat aortic vascular endothelial cells stimulated by inflammatory tenocytes via modulating the NLRP3 pathway
  61. Cord-lamina angle and foraminal diameter as key predictors of C5 palsy after anterior cervical decompression and fusion surgery
  62. GATA1: A key biomarker for predicting the prognosis of patients with diffuse large B-cell lymphoma
  63. Influencing factors of false lumen thrombosis in type B aortic dissection: A single-center retrospective study
  64. MZB1 regulates the immune microenvironment and inhibits ovarian cancer cell migration
  65. Integrating experimental and network pharmacology to explore the pharmacological mechanisms of Dioscin against glioblastoma
  66. Trends in research on preterm birth in twin pregnancy based on bibliometrics
  67. Four-week IgE/baseline IgE ratio combined with tryptase predicts clinical outcome in omalizumab-treated children with moderate-to-severe asthma
  68. Single-cell transcriptomic analysis identifies a stress response Schwann cell subtype
  69. Acute pancreatitis risk in the diagnosis and management of inflammatory bowel disease: A critical focus
  70. Effect of subclinical esketamine on NLRP3 and cognitive dysfunction in elderly ischemic stroke patients
  71. Interleukin-37 mediates the anti-oral tumor activity in oral cancer through STAT3
  72. CA199 and CEA expression levels, and minimally invasive postoperative prognosis analysis in esophageal squamous carcinoma patients
  73. Efficacy of a novel drainage catheter in the treatment of CSF leak after posterior spine surgery: A retrospective cohort study
  74. Comprehensive biomedicine assessment of Apteranthes tuberculata extracts: Phytochemical analysis and multifaceted pharmacological evaluation in animal models
  75. Relation of time in range to severity of coronary artery disease in patients with type 2 diabetes: A cross-sectional study
  76. Dopamine attenuates ethanol-induced neuronal apoptosis by stimulating electrical activity in the developing rat retina
  77. Correlation between albumin levels during the third trimester and the risk of postpartum levator ani muscle rupture
  78. Factors associated with maternal attention and distraction during breastfeeding and childcare: A cross-sectional study in the west of Iran
  79. Mechanisms of hesperetin in treating metabolic dysfunction-associated steatosis liver disease via network pharmacology and in vitro experiments
  80. The law on oncological oblivion in the Italian and European context: How to best uphold the cancer patients’ rights to privacy and self-determination?
  81. The prognostic value of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and prognostic nutritional index for survival in patients with colorectal cancer
  82. Factors affecting the measurements of peripheral oxygen saturation values in healthy young adults
  83. Comparison and correlations between findings of hysteroscopy and vaginal color Doppler ultrasonography for detection of uterine abnormalities in patients with recurrent implantation failure
  84. The effects of different types of RAGT on balance function in stroke patients with low levels of independent walking in a convalescent rehabilitation hospital
  85. Causal relationship between asthma and ankylosing spondylitis: A bidirectional two-sample univariable and multivariable Mendelian randomization study
  86. Correlations of health literacy with individuals’ understanding and use of medications in Southern Taiwan
  87. Correlation of serum calprotectin with outcome of acute cerebral infarction
  88. Comparison of computed tomography and guided bronchoscopy in the diagnosis of pulmonary nodules: A systematic review and meta-analysis
  89. Curdione protects vascular endothelial cells and atherosclerosis via the regulation of DNMT1-mediated ERBB4 promoter methylation
  90. The identification of novel missense variant in ChAT gene in a patient with gestational diabetes denotes plausible genetic association
  91. Molecular genotyping of multi-system rare blood types in foreign blood donors based on DNA sequencing and its clinical significance
  92. Exploring the role of succinyl carnitine in the association between CD39⁺ CD4⁺ T cell and ulcerative colitis: A Mendelian randomization study
  93. Dexmedetomidine suppresses microglial activation in postoperative cognitive dysfunction via the mmu-miRNA-125/TRAF6 signaling axis
  94. Analysis of serum metabolomics in patients with different types of chronic heart failure
  95. Diagnostic value of hematological parameters in the early diagnosis of acute cholecystitis
  96. Pachymaran alleviates fat accumulation, hepatocyte degeneration, and injury in mice with nonalcoholic fatty liver disease
  97. Decrease in CD4 and CD8 lymphocytes are predictors of severe clinical picture and unfavorable outcome of the disease in patients with COVID-19
  98. METTL3 blocked the progression of diabetic retinopathy through m6A-modified SOX2
  99. The predictive significance of anti-RO-52 antibody in patients with interstitial pneumonia after treatment of malignant tumors
  100. Exploring cerebrospinal fluid metabolites, cognitive function, and brain atrophy: Insights from Mendelian randomization
  101. Development and validation of potential molecular subtypes and signatures of ocular sarcoidosis based on autophagy-related gene analysis
  102. Widespread venous thrombosis: Unveiling a complex case of Behçet’s disease with a literature perspective
  103. Uterine fibroid embolization: An analysis of clinical outcomes and impact on patients’ quality of life
  104. Discovery of lipid metabolism-related diagnostic biomarkers and construction of diagnostic model in steroid-induced osteonecrosis of femoral head
  105. Serum-derived exomiR-188-3p is a promising novel biomarker for early-stage ovarian cancer
  106. Enhancing chronic back pain management: A comparative study of ultrasound–MRI fusion guidance for paravertebral nerve block
  107. Peptide CCAT1-70aa promotes hepatocellular carcinoma proliferation and invasion via the MAPK/ERK pathway
  108. Electroacupuncture-induced reduction of myocardial ischemia–reperfusion injury via FTO-dependent m6A methylation modulation
  109. Hemorrhoids and cardiovascular disease: A bidirectional Mendelian randomization study
  110. Cell-free adipose extract inhibits hypertrophic scar formation through collagen remodeling and antiangiogenesis
  111. HALP score in Demodex blepharitis: A case–control study
  112. Assessment of SOX2 performance as a marker for circulating cancer stem-like cells (CCSCs) identification in advanced breast cancer patients using CytoTrack system
  113. Risk and prognosis for brain metastasis in primary metastatic cervical cancer patients: A population-based study
  114. Comparison of the two intestinal anastomosis methods in pediatric patients
  115. Factors influencing hematological toxicity and adverse effects of perioperative hyperthermic intraperitoneal vs intraperitoneal chemotherapy in gastrointestinal cancer
  116. Endotoxin tolerance inhibits NLRP3 inflammasome activation in macrophages of septic mice by restoring autophagic flux through TRIM26
  117. Lateral transperitoneal laparoscopic adrenalectomy: A single-centre experience of 21 procedures
  118. Petunidin attenuates lipopolysaccharide-induced retinal microglia inflammatory response in diabetic retinopathy by targeting OGT/NF-κB/LCN2 axis
  119. Procalcitonin and C-reactive protein as biomarkers for diagnosing and assessing the severity of acute cholecystitis
  120. Factors determining the number of sessions in successful extracorporeal shock wave lithotripsy patients
  121. Development of a nomogram for predicting cancer-specific survival in patients with renal pelvic cancer following surgery
  122. Inhibition of ATG7 promotes orthodontic tooth movement by regulating the RANKL/OPG ratio under compression force
  123. A machine learning-based prognostic model integrating mRNA stemness index, hypoxia, and glycolysis‑related biomarkers for colorectal cancer
  124. Glutathione attenuates sepsis-associated encephalopathy via dual modulation of NF-κB and PKA/CREB pathways
  125. FAHD1 prevents neuronal ferroptosis by modulating R-loop and the cGAS–STING pathway
  126. Association of placenta weight and morphology with term low birth weight: A case–control study
  127. Investigation of the pathogenic variants induced Sjogren’s syndrome in Turkish population
  128. Nucleotide metabolic abnormalities in post-COVID-19 condition and type 2 diabetes mellitus patients and their association with endocrine dysfunction
  129. TGF-β–Smad2/3 signaling in high-altitude pulmonary hypertension in rats: Role and mechanisms via macrophage M2 polarization
  130. Ultrasound-guided unilateral versus bilateral erector spinae plane block for postoperative analgesia of patients undergoing laparoscopic cholecystectomy
  131. Profiling gut microbiome dynamics in subacute thyroiditis: Implications for pathogenesis, diagnosis, and treatment
  132. Delta neutrophil index, CRP/albumin ratio, procalcitonin, immature granulocytes, and HALP score in acute appendicitis: Best performing biomarker?
  133. Anticancer activity mechanism of novelly synthesized and characterized benzofuran ring-linked 3-nitrophenyl chalcone derivative on colon cancer cells
  134. H2valdien3 arrests the cell cycle and induces apoptosis of gastric cancer
  135. Prognostic relevance of PRSS2 and its immune correlates in papillary thyroid carcinoma
  136. Association of SGLT2 inhibition with psychiatric disorders: A Mendelian randomization study
  137. Motivational interviewing for alcohol use reduction in Thai patients
  138. Luteolin alleviates oxygen-glucose deprivation/reoxygenation-induced neuron injury by regulating NLRP3/IL-1β signaling
  139. Polyphyllin II inhibits thyroid cancer cell growth by simultaneously inhibiting glycolysis and oxidative phosphorylation
  140. Relationship between the expression of copper death promoting factor SLC31A1 in papillary thyroid carcinoma and clinicopathological indicators and prognosis
  141. CSF2 polarized neutrophils and invaded renal cancer cells in vitro influence
  142. Proton pump inhibitors-induced thrombocytopenia: A systematic literature analysis of case reports
  143. The current status and influence factors of research ability among community nurses: A sequential qualitative–quantitative study
  144. OKAIN: A comprehensive oncology knowledge base for the interpretation of clinically actionable alterations
  145. The relationship between serum CA50, CA242, and SAA levels and clinical pathological characteristics and prognosis in patients with pancreatic cancer
  146. Identification and external validation of a prognostic signature based on hypoxia–glycolysis-related genes for kidney renal clear cell carcinoma
  147. Engineered RBC-derived nanovesicles functionalized with tumor-targeting ligands: A comparative study on breast cancer targeting efficiency and biocompatibility
  148. Relationship of resting echocardiography combined with serum micronutrients to the severity of low-gradient severe aortic stenosis
  149. Effect of vibration on pain during subcutaneous heparin injection: A randomized, single-blind, placebo-controlled trial
  150. The diagnostic performance of machine learning-based FFRCT for coronary artery disease: A meta-analysis
  151. Comparing biofeedback device vs diaphragmatic breathing for bloating relief: A randomized controlled trial
  152. Serum uric acid to albumin ratio and C-reactive protein as predictive biomarkers for chronic total occlusion and coronary collateral circulation quality
  153. Multiple organ scoring systems for predicting in-hospital mortality of sepsis patients in the intensive care unit
  154. Single-cell RNA sequencing data analysis of the inner ear in gentamicin-treated mice via intraperitoneal injection
  155. Review Articles
  156. The effects of enhanced external counter-pulsation on post-acute sequelae of COVID-19: A narrative review
  157. Diabetes-related cognitive impairment: Mechanisms, symptoms, and treatments
  158. Microscopic changes and gross morphology of placenta in women affected by gestational diabetes mellitus in dietary treatment: A systematic review
  159. Review of mechanisms and frontier applications in IL-17A-induced hypertension
  160. Research progress on the correlation between islet amyloid peptides and type 2 diabetes mellitus
  161. The safety and efficacy of BCG combined with mitomycin C compared with BCG monotherapy in patients with non-muscle-invasive bladder cancer: A systematic review and meta-analysis
  162. The application of augmented reality in robotic general surgery: A mini-review
  163. The effect of Greek mountain tea extract and wheat germ extract on peripheral blood flow and eicosanoid metabolism in mammals
  164. Neurogasobiology of migraine: Carbon monoxide, hydrogen sulfide, and nitric oxide as emerging pathophysiological trinacrium relevant to nociception regulation
  165. Plant polyphenols, terpenes, and terpenoids in oral health
  166. Laboratory medicine between technological innovation, rights safeguarding, and patient safety: A bioethical perspective
  167. End-of-life in cancer patients: Medicolegal implications and ethical challenges in Europe
  168. The maternal factors during pregnancy for intrauterine growth retardation: An umbrella review
  169. Intra-abdominal hypertension/abdominal compartment syndrome of pediatric patients in critical care settings
  170. PI3K/Akt pathway and neuroinflammation in sepsis-associated encephalopathy
  171. Screening of Group B Streptococcus in pregnancy: A systematic review for the laboratory detection
  172. Giant borderline ovarian tumours – review of the literature
  173. Leveraging artificial intelligence for collaborative care planning: Innovations and impacts in shared decision-making – A systematic review
  174. Cholera epidemiology analysis through the experience of the 1973 Naples epidemic
  175. Risk factors of frailty/sarcopenia in community older adults: Meta-analysis
  176. Supplement strategies for infertility in overweight women: Evidence and legal insights
  177. Scurvy, a not obsolete disorder: Clinical report in eight young children and literature review
  178. A meta-analysis of the effects of DBS on cognitive function in patients with advanced PD
  179. Protective role of selenium in sepsis: Mechanisms and potential therapeutic strategies
  180. Strategies for hyperkalemia management in dialysis patients: A systematic review
  181. C-reactive protein-to-albumin ratio in peripheral artery disease
  182. Case Reports
  183. Delayed graft function after renal transplantation
  184. Semaglutide treatment for type 2 diabetes in a patient with chronic myeloid leukemia: A case report and review of the literature
  185. Diverse electrophysiological demyelinating features in a late-onset glycogen storage disease type IIIa case
  186. Giant right atrial hemangioma presenting with ascites: A case report
  187. Laser excision of a large granular cell tumor of the vocal cord with subglottic extension: A case report
  188. EsoFLIP-assisted dilation for dysphagia in systemic sclerosis: Highlighting the role of multimodal esophageal evaluation
  189. Molecular hydrogen-rhodiola as an adjuvant therapy for ischemic stroke in internal carotid artery occlusion: A case report
  190. Coronary artery anomalies: A case of the “malignant” left coronary artery and its surgical management
  191. Rapid Communication
  192. Biological properties of valve materials using RGD and EC
  193. A single oral administration of flavanols enhances short-term memory in mice along with increased brain-derived neurotrophic factor
  194. Letter to the Editor
  195. Role of enhanced external counterpulsation in long COVID
  196. Expression of Concern
  197. Expression of concern “A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma”
  198. Expression of concern “Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway”
  199. Expression of concern “circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8”
  200. Corrigendum
  201. Corrigendum to “Empagliflozin improves aortic injury in obese mice by regulating fatty acid metabolism”
  202. Corrigendum to “Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis”
  203. Corrigendum to “The progress of autoimmune hepatitis research and future challenges”
  204. Retraction
  205. Retraction of “miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway”
  206. Retraction of: “LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through downregulating SP-A by sponging to miR-424”
  207. Retraction of: “SCARA5 inhibits oral squamous cell carcinoma via inactivating the STAT3 and PI3K/AKT signaling pathways”
  208. Special Issue Advancements in oncology: bridging clinical and experimental research - Part II
  209. Unveiling novel biomarkers for platinum chemoresistance in ovarian cancer
  210. Lathyrol affects the expression of AR and PSA and inhibits the malignant behavior of RCC cells
  211. The era of increasing cancer survivorship: Trends in fertility preservation, medico-legal implications, and ethical challenges
  212. Bone scintigraphy and positron emission tomography in the early diagnosis of MRONJ
  213. Meta-analysis of clinical efficacy and safety of immunotherapy combined with chemotherapy in non-small cell lung cancer
  214. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part IV
  215. Exploration of mRNA-modifying METTL3 oncogene as momentous prognostic biomarker responsible for colorectal cancer development
  216. Special Issue The evolving saga of RNAs from bench to bedside - Part III
  217. Interaction and verification of ferroptosis-related RNAs Rela and Stat3 in promoting sepsis-associated acute kidney injury
  218. The mRNA MOXD1: Link to oxidative stress and prognostic significance in gastric cancer
  219. Special Issue Exploring the biological mechanism of human diseases based on MultiOmics Technology - Part II
  220. Dynamic changes in lactate-related genes in microglia and their role in immune cell interactions after ischemic stroke
  221. A prognostic model correlated with fatty acid metabolism in Ewing’s sarcoma based on bioinformatics analysis
  222. Red cell distribution width predicts early kidney injury: A NHANES cross-sectional study
  223. Special Issue Diabetes mellitus: pathophysiology, complications & treatment
  224. Nutritional risk assessment and nutritional support in children with congenital diabetes during surgery
  225. Correlation of the differential expressions of RANK, RANKL, and OPG with obesity in the elderly population in Xinjiang
  226. A discussion on the application of fluorescence micro-optical sectioning tomography in the research of cognitive dysfunction in diabetes
  227. A review of brain research on T2DM-related cognitive dysfunction
  228. Metformin and estrogen modulation in LABC with T2DM: A 36-month randomized trial
  229. Special Issue Innovative Biomarker Discovery and Precision Medicine in Cancer Diagnostics
  230. CircASH1L-mediated tumor progression in triple-negative breast cancer: PI3K/AKT pathway mechanisms
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