Brains are highly energy-demanding organs that require sufficient energy to sustain normal functional activities (26). A decline in brain metabolism has been implicated in the development of POD (27). Specifically, during delirium episodes, cortical glucose metabolism is markedly reduced, with partial recovery observed as delirium symptoms subside. In support of this, Caplan et al (28) observed increased anaerobic metabolism in the brains of patients with delirium, characterized by elevated cerebrospinal fluid lactate levels and decreased neuron-specific enolase concentrations, suggesting metabolic stress. Furthermore, with aging, pathological and physiological changes occur in cerebral blood vessels, leading to impaired brain perfusion and vascular reactivity (29,30). Multiple studies have demonstrated that reduced cerebral perfusion may contribute to cognitive and learning impairments. For instance, using computed tomography, Yokota et al (31) and Aa et al (32) identified notably decreased cerebral perfusion in patients with delirium, which returned to normal following symptom resolution. Consistently, numerous studies have confirmed that individuals with preoperative cognitive impairment or diminished cognitive reserve, such as those with dementia or mild cognitive impairment, are at a higher risk of developing POD after surgery (33–35).

Neuroinflammation is a key characteristic of all neurological complications (20). Surgical procedures cause extensive tissue damage, ischemia-reperfusion injury and hypoperfusion due to pronounced blood loss. These factors collectively lead to the excessive release of inflammatory mediators, triggering a systemic inflammatory response that impairs multiple organ functions, including those of the brain (36,37). One major consequence of this inflammatory cascade is the disruption of the blood-brain barrier (BBB). The excessive release of C-reactive protein and pro-inflammatory cytokines, such as IL-1β, IL-6 and TNF-α, damages endothelial cells, reduces the expression of tight junction proteins and increases BBB permeability (38). As a result, peripheral inflammatory mediators infiltrate the brain parenchyma, further enhancing the activation of microglia and astrocytes. Once activated, microglia perpetuate neuroinflammation by producing nitric oxide, which leads to DNA deamination and neuronal apoptosis, as well as the production of reactive oxygen species, which causes lipid peroxidation (30,37,39). These processes collectively contribute to neuronal and synaptic dysfunction, ultimately promoting the development of POD. In addition to direct neuronal damage, surgery-induced neuroinflammation negatively impacts neuroplasticity; it downregulates brain-derived neurotrophic factor (BDNF) and its receptors, inhibiting downstream signaling pathways essential for neurogenesis, synaptogenesis, learning and memory (36). Moreover, a study has revealed that surgical stress disrupts hippocampal iron homeostasis, leading to iron accumulation. This iron overload exacerbates oxidative stress, intensifies neuroinflammation and further impairs cognitive function (40). Supporting this inflammatory hypothesis, a study by Glumac et al (41) demonstrated that preoperative corticosteroid administration effectively attenuates the systemic inflammatory response and improves postoperative cognitive outcomes, highlighting inflammation as a key factor in the pathogenesis of POD.

Extracellular Aβ plaques, tau hyperphosphorylation and neurofibrillary tangles (NFTs) formed by tau aggregation are major pathological hallmarks of neurodegenerative diseases, particularly Alzheimer's disease (AD) (42). Studies suggest that POD shares a similar pathological basis with AD (43,44). Aβ protein readily aggregates in brain tissue, forming highly toxic oligomers that induce neuronal death and synaptic damage. Moreover, Aβ oligomers disrupt central nervous system insulin signaling, thereby interfering with brain energy metabolism and further exacerbating neurodegeneration (45). Tau protein, a microtubule-associated protein, plays a key role in microtubule assembly, stabilization and axonal transport; it is essential for regulating neuronal growth, development and signal transmission (42,44). However, surgery and anesthesia have been revealed to induce tau hyperphosphorylation, leading to structural and functional abnormalities (46,47). Hyperphosphorylated tau proteins further aggregate and precipitate, forming NFTs, which are sensitive biomarkers of axonal injury in the central nervous system (48,49). Notably, elevated levels of NFTs in cerebrospinal fluid and blood have been associated with POD (50). Aβ and abnormally phosphorylated tau proteins act synergistically to influence the onset and progression of POD. Aβ oligomers promote tau phosphorylation by increasing GSK-3β activity. Additionally, both of them collectively activate microglia and astrocytes, triggering the release of various inflammatory cytokines (51–53). These inflammatory mediators further accelerate tau hyperphosphorylation and Aβ oligomerization, ultimately leading to neuronal damage and the development of POD.

Sleep is key for neurodevelopment and the maintenance of brain function. Studies suggest that perioperative sleep disturbances are associated with the occurrence of POD (54–56). Various perioperative factors, including trauma, anesthesia, stress, pain and inflammation, can disrupt the sleep-wake regulatory system and circadian rhythm, further contributing to postoperative neurocognitive dysfunction. Multiple studies have demonstrated that patients with delirium exhibit a pronounced reduction in the rapid eye movement phase of sleep, increased sleep fragmentation and heightened wakefulness (57–59). Sleep disturbances lead to hyperactivation of the hypothalamic-pituitary-adrenal axis, resulting in excessive cortisol secretion. Elevated cortisol levels inhibit neuronal glucose uptake, making neurons metabolically vulnerable to oxidative stress. This process contributes to neuronal loss, alterations in dendritic spine density and changes in synaptic number, morphology and function, ultimately leading to cognitive impairment (56,60,61). Additionally, sleep deprivation increases the release of inflammatory cytokines, activates microglia and exacerbates neuroinflammatory responses (62,63). Fultz et al (64) further revealed that disruptions in the sleep-wake cycle dysregulate aquaporin-4 expression levels, impairing the glymphatic system and hindering cerebrospinal fluid clearance of Aβ protein. These pathological changes suggest that disturbances in the sleep-wake cycle contribute to POD development through multiple interrelated pathways. Notably, in patients of postoperative cardiac surgery, sleep deprivation consistently precedes the onset of delirium. Furthermore, patients in the ICU experiencing sleep deprivation are markedly more likely to develop delirium compared with those with adequate sleep (65).

Olfactory signals are transmitted via the olfactory filaments, olfactory bulb and olfactory tract to the primary olfactory cortex, from where they further project to brain regions, including the insula, hypothalamus and hippocampus (66). Notably, certain olfactory centers and the hippocampus exhibit synchronized electrophysiological activity and directly participate in memory processes, highlighting the functional interplay between olfaction and cognition (67). Emerging evidence suggests that anesthesia and surgery can impair both olfactory and cognitive functions. Zhang et al (24) revealed that anesthesia and surgery lead to deficits in olfaction and cognition in mice, while olfactory stimulation reverses these effects by restoring the expression of olfactory marker protein 13 and growth-associated protein 43, and by preventing the reduction of hippocampal synaptic markers postsynaptic density protein (PSD)-95 and synaptophysin. Clinical studies further support this finding. Kamath et al (68) discovered that preoperative olfactory dysfunction is associated with both the incidence and severity of POD, suggesting that olfactory assessment could serve as a valuable preoperative screening tool for identifying high-risk patients with POD. Similarly, in the study by Yang et al (69), 14 out of 21 (66.67%) patients with preoperative olfactory dysfunction exhibited postoperative cognitive dysfunction, providing additional evidence of the association between olfactory function and cognitive performance. Mechanistically, research has indicated that olfactory and cognitive processing centers share overlapping neural pathways, with the cholinergic system carrying out a central role in both olfactory transmission and cognitive function. Dopamine and acetylcholine serve as key neurotransmitters regulating both cognition and olfaction. Given these interconnections, olfactory impairment may contribute to the development of POD by disrupting shared neurochemical and neural circuits (70,71).

Previous studies have revealed that alterations in gut microbiota are associated with abnormal cognitive behaviors. The gut microbiota carries out a key role in regulating neural functions in the brain through multiple pathways, including immune modulation and neuroendocrine regulation, thereby influencing cognitive processes (72–74). Anesthesia and surgery induce gut microbiota dysbiosis, which is primarily characterized by a notable reduction in microbial abundance and diversity, particularly with aging (75). This dysbiosis exacerbates systemic inflammation, increases gut permeability and subsequently compromises the integrity of the BBB, ultimately leading to disruptions in brain immune homeostasis. Furthermore, gut microbiota can produce Aβ protein, which, despite having a different primary structure from brain-derived Aβ, shares a highly similar tertiary structure. This structural similarity suggests that gut microbiota dysbiosis may contribute to the abnormal deposition of Aβ and tau proteins, potentially triggering cross-immune reactions and excessive activation of pro-inflammatory signaling pathways in the brain (76). In addition to its role in protein aggregation, gut microbiota dysbiosis also alters neurotransmitter levels, including γ-aminobutyric acid, 5-hydroxytryptamine, dopamine and acetylcholine, thereby affecting central nervous system function (74,77). Notably, disruptions in gut microbiota composition can induce neuropsychiatric symptoms such as anxiety and depression, which may accelerate cognitive decline by further impairing neural function (78,79).

EEG burst suppression is a common neurophysiological phenomenon observed during clinical anesthesia, characterized by alternating high-amplitude burst activity and periods of isoelectric suppression on EEG. Notably, the occurrence of POD is associated with the depth of general anesthesia, as excessive anesthetic depth increases the likelihood of EEG burst suppression, which in turn elevates the risk of POD (80). Clinical studies have demonstrated this association (81–83). In a study of spinal fixation surgery under total intravenous anesthesia, 78 patients (69.6%) exhibited intraoperative burst suppression (BS), while 10 patients (8.9%) developed POD. All cases of POD occurred in patients who experienced intraoperative BS, and prolonged BS duration was observed in these individuals (84). Further research has indicated a quantitative relationship between BS duration and risk of POD, with each additional minute of intraoperative BS doubling the likelihood of developing POD. Given this evidence, intraoperative BS has been proposed as a potential predictor of POD, highlighting the importance of anesthetic depth monitoring to mitigate the risk of POD (85).

In recent years, the genetic hypothesis of delirium susceptibility has emerged as a promising research direction. Studies have identified associations between POD and several genetic factors, including APOE4, the dopamine transporter gene SCL6A3, the dopamine receptor 2 gene, the glucocorticoid receptor, the melatonin receptor and mitochondrial DNA haplotypes (86–88). Additionally, two long intergenic non-coding RNA genes with potential functional implications have been revealed, further expanding the understanding of the genetic basis of POD (89).

The Wnt signaling pathway consists of one canonical and two non-canonical pathways, which enhance synaptic plasticity, promote neuronal survival and regulate cell death, thereby carrying out a key role in brain function (91). Notably, studies have revealed that the canonical Wnt/β-catenin pathway is involved in the pathogenesis of POD. In a study on Sprague-Dawley rats, exposure to 3% sevoflurane for 6 h resulted in cognitive impairment, downregulation of β-catenin and phosphorylated GSK-3β in the hippocampus, increased levels of TNF-α and IL-1, and structural damage to hippocampal neurons. These findings suggest that sevoflurane suppresses Wnt/β-catenin signaling, activates inflammatory responses and induces hippocampal injury, ultimately contributing to POD development (92). Notably, this damage was reversed upon exogenous administration of lithium chloride, an activator of the Wnt/β-catenin pathway. Further supporting the role of Wnt/β-catenin signaling in POD, a study on endothelial cells have shown that exposure to 3% sevoflurane for 6 h downregulates Wnt/β-catenin activity, leading to reduced Annexin A1 expression, disruption of the BBB and subsequent POD onset (93). Similarly, in transgenic mice, overexpression of DKK-1 inhibits the Wnt/β-catenin pathway, promoting excessive tau protein phosphorylation and cognitive impairment. Conversely, activation of the Wnt/β-catenin pathway suppresses inflammatory responses and improves cognitive function, suggesting its potential as a therapeutic target for POD prevention and treatment (94).

Key roles are conducted by the PI3K/AKT signaling pathway, including cell growth, proliferation, differentiation and apoptosis. PI3K functions as a key intracellular signaling molecule, while AKT serves as its primary downstream protein kinase. Upon activation, PI3K further phosphorylates AKT, which in turn further phosphorylates key downstream targets, including GSK-3β, mTOR, endothelial nitric oxide synthase, FoxO3a and NF-κB, thereby regulating physiological processes such as cell growth, proliferation, cell cycle progression and glucose metabolism (95,96).

GSK-3 is a key substrate of AKT and exists in two isoforms in the brain: GSK-3α and GSK-3β. Among them, GSK-3β is widely expressed in the central nervous system and is implicated in the pathological mechanisms underlying cognitive decline in neurodegenerative diseases (96). GSK-3β is a key kinase responsible for tau phosphorylation. Both animal and clinical studies have demonstrated a positive association between the abnormal upregulation of GSK-3β, tau phosphorylation and the accumulation of toxic tau aggregates (97–99). Notably, increased levels of GSK-3β and phosphorylated tau have been observed in rodent brain tissues following anesthesia and surgery, further supporting its role in postoperative neurocognitive impairment. Beyond tau pathology, GSK-3β activation has been revealed to contribute to Aβ formation and accumulation in the brain by regulating amyloid precursor protein cleavage (51). Additionally, it can induce Aβ pathology by disrupting insulin signaling pathways (100). Studies have proposed a feedback loop between Aβ and GSK-3β activation, where sustained interactions in specific pathways may exacerbate tau hyperphosphorylation and neurotoxicity (101–103). GSK-3β is also involved in neuroinflammation. The activation of GSK-3β promotes the production of IL-1, IL-6 and TNF-α, activates the JNK, STAT3/5, and NF-κB signaling pathways, and regulates microglial migration, contributing to inflammatory responses in the brain (104). Furthermore, GSK-3β has been implicated in the suppression of adult hippocampal neurogenesis. The excessive activation of GSK-3β impairs long-term potentiation and enhances N-methyl-D-aspartate receptor-dependent long-term depression, thereby disrupting synaptic plasticity, memory formation and neurogenesis. These mechanisms collectively suggest that GSK-3β overactivation may play a key role in the pathogenesis of POD (51).

mTOR is an atypical serine/threonine kinase that plays a key role in cell growth, proliferation, protein synthesis and autophagy. As a major downstream target of the PI3K/AKT signaling pathway, mTOR serves as the principal negative regulator of autophagy, a process essential for cell survival, development, division and homeostasis (105). Autophagy has a dual role in neural function. First, it facilitates the clearance and degradation of Aβ protein. In both cellular and animal models, autophagy activators, such as mTOR inhibitors, have been revealed to reduce tau hyperphosphorylation and the misfolding of other aggregated proteins by promoting the autophagic degradation of NFTs and Aβ plaques (106). Secondly, autophagy is involved in synaptic plasticity and neurotransmission, highlighting its broader role in cognitive function.

Gao et al (107) demonstrated that anesthesia and surgery impair reference memory while inducing mTOR activation, as evidenced by increased levels of phosphorylated mTOR and decreased expression of autophagy-related proteins such as Beclin-1 and LC3-II. Additionally, neuronal and synaptic plasticity-associated proteins (such as Synaptophysin and PSD-95) were downregulated. Notably, pretreatment with rapamycin suppressed mTOR activation, restored autophagy and reversed anesthesia/surgery-induced learning and memory deficits. Despite its beneficial roles, excessive autophagy can be detrimental, as it may disrupt normal organelle function, leading to cellular dysfunction or cell death. The PI3K/AKT/mTOR signaling pathway exerts bidirectional effects on neuronal cells, where both overactivation and inhibition can contribute to cognitive decline (96,108). Pharmacological modulation of this pathway has demonstrated promise in protecting cognitive function. Dexmedetomidine and esketamine activate the PI3K/AKT/mTOR pathway, alleviating neuroinflammatory responses in brain tissue, inhibiting neuronal apoptosis and ultimately preserving postoperative cognitive function (109,110).

The PI3K/AKT signaling pathway has been extensively studied in neurological diseases, with numerous associated pathways being explored. In addition to those previously discussed, other pathways, such as PI3K/AKT/Nrf2, PI3K/AKT/CREB and PI3K/AKT/MAPK, have been identified. These interconnected pathways regulate a range of neurophysiological and pathological processes, including mitochondrial function restoration, abnormal protein clearance, cerebrovascular regeneration and synaptic plasticity enhancement (111–113).

BDNF is the most abundant neurotrophic factor in the brain, playing a key role in regions responsible for learning, memory and higher cognitive functions, such as the hippocampus, cerebral cortex and basal forebrain (114). Dysregulation of BDNF and its downstream pathways may lead to abnormal neuronal differentiation, synaptic loss and cognitive dysfunction, suggesting that the BDNF/TrkB signaling pathway may be involved in the pathogenesis of POD. Qiu et al (115) demonstrated that anesthesia and surgery induce microglial activation, IL-1β release and BDNF downregulation in the hippocampus, resulting in hippocampus-dependent cognitive impairment in aged mice. Subsequent studies have also reported a notable reduction in total TrkB expression (114,116,117). Similarly, Fan et al (118) revealed that surgery reduces BDNF expression and neurogenesis while also decreasing phosphorylated/activated TrkB and ERK expression. However, this study observed no significant impact on total TrkB expression levels. This discrepancy may be attributed to differences in surgical procedures, mouse age and tissue collection time points. In addition to its role in neurogenesis, the BDNF/TrkB pathway is also key for synaptic plasticity and neuronal growth. Notably, the BDNF/proBDNF ratio carries out a key role in regulating synaptic plasticity (119). Jia et al (117) revealed that exposure to 3% sevoflurane markedly inhibited the proliferation of neural stem cells, immature neurons and newly formed neurons, which was accompanied by reduced BDNF and TrkB protein expression. Furthermore, studies have suggested that the BDNF/TrkB signaling pathway is involved in Aβ aggregation and tau protein phosphorylation (119–121). Activation of this pathway has been revealed to reduce tau phosphorylation levels and enhance learning and memory abilities, highlighting its potential as a therapeutic target for neurodegenerative diseases and POD.

TLR signaling involves at least two distinct pathways: The MyD88-dependent and MyD88-independent pathways (122). The MyD88-dependent pathway is the primary TLR signaling cascade, transmitting signals through two major activation routes: The MAPK and NF-κB pathways. Both pathways regulate the transcription of inflammatory factors, leading to excessive cytokine release, which ultimately affects the central nervous system and contributes to cognitive dysfunction (123). Among the TLR family, TLR4 is highly expressed in microglial cells and serves as a key receptor for microglial activation and function (122). Lu et al (124) subjected rats to tibial fracture surgery and observed increased expression of S100A8 and S100A9, along with hippocampal TLR4/MyD88 activation. This pro-inflammatory response was associated with the onset of POD. Similarly, in aged rats undergoing splenectomy, TLR4 activation was detected, accompanied by elevated levels of inflammatory mediators such as IL-6 and IL-1β, which triggered central neuroinflammation (125). Beyond TLR4, other TLR family members have also been implicated in surgery-induced neuroinflammation and cognitive dysfunction. Lin et al (126) conducted anesthesia and surgery on both TLR2-knockout and wild-type mice, assessing their learning and memory abilities. The findings suggested that TLR2 contributes to surgery-induced neuroinflammation and cognitive impairment. A study by Yang et al (127) demonstrated that inhibition of the TLR2/TLR4 signaling pathway suppresses hippocampal neuroinflammatory cytokines and alleviates postoperative cognitive dysfunction in rats. Chen et al (128) revealed that extracellular RNAs-TLR3 carries out a role in learning and memory deficits following nephrectomy in mice. Additionally, a recent study indicated that TLR7 is involved in anesthesia- and surgery-induced cognitive dysfunction (129). Collectively, these findings suggest that TLR signaling pathways carry out a key role in the development of POD, highlighting their potential as therapeutic targets for intervention.

The MAPK signaling pathway mediates specific biological functions such as cell proliferation, differentiation and survival, encompassing the p38 MAPK pathway, the JNK pathway and the ERK pathway (130).

p38 MAPK, also known as a stress-activated protein kinase, regulates key cellular processes, including cell proliferation, differentiation, survival and stress-induced apoptosis. Evidence suggests that its dysregulation carries out a key role in cognitive impairment and neuroinflammation (131). Lv et al (132) demonstrated that mice subjected to exploratory laparotomy exhibited cognitive deficits, with both pathological analysis and western blotting results consistently demonstrating increased phosphorylated (p)-p38 expression. Similarly, Song et al (131) conducted a study on neonates exposed to sevoflurane and found a time-dependent upregulation of p-p38 and p-p65, as well as the p-p38/p38 and p-p65/p65 ratios. Beyond its involvement in neuroinflammatory responses, p38 MAPK directly modulates GSK-3β activity, leading to increased GSK-3β kinase function, which in turn promotes tau hyperphosphorylation and impairs synaptic plasticity (133). Studies have demonstrated that activation of the p38 MAPK signaling pathway contributes to the onset of POD (131–133). Conversely, inhibition of p-p38 expression has been revealed to mitigate POD symptoms (134).

The JNK pathway has a key role in transmitting extracellular signals to the nucleus and is involved in various biological processes, including cytokine regulation and inhibition of protein synthesis (135). JNK is classified into three isoforms: JNK1, JNK2 and JNK3. Among them, JNK3 is highly expressed and activated in the brain tissue and cerebrospinal fluid of patients with delirium, with a notable association with the rate of cognitive decline (136). In a study by Li et al (137), exposure to isoflurane led to increased expression of p-JNK and p-c-Jun, suggesting that JNK pathway activation contributes to isoflurane-induced neuroapoptosis in the developing brain. Similarly, Bi et al (138) revealed that sevoflurane activates the JNK/c-Jun/AP-1 signaling pathway, which in turn upregulates the apoptotic factor connexin 43, leading to neuronal apoptosis. Yang et al (139) noted that JNK signaling may have a key role in the reduced survival rate of fetal neural stem cells induced by sevoflurane. Notably, inhibition of the JNK pathway has been revealed to mitigate neuronal apoptosis and exert neuroprotective effects (140).

ERK is a key regulator of pro-inflammatory microglial activation, and its signaling pathway carries out a key role in reducing oxidative stress and exerting neuroprotective effects in POD (141). The ERK phosphorylation status is associated with anesthesia-induced neurotoxicity. Yufune et al (142) observed that oxidative stress-mediated inhibition of ERK phosphorylation serves as a fundamental mechanism underlying sevoflurane-induced neurotoxicity. Numerous studies have demonstrated that anesthetics such as sevoflurane, ketamine and propofol suppress the ERK1/2 signaling pathway, leading to neuronal apoptosis in the developing brain (143–145). Conversely, certain studies have confirmed that restoring ERK phosphorylation can counteract anesthetic-induced neuronal apoptosis (143–146). Lithium, N-stearoyl-L-tyrosine, the phosphodiesterase-4 inhibitor, roflumilast, and electroacupuncture pretreatment have all been demonstrated to attenuate anesthetic-induced neuronal apoptosis and improve cognitive function by upregulating ERK signaling. Several studies have underscored the key role of the ERK signaling pathway in neuronal growth, survival and synaptic plasticity (147,148).

NF-κB is a transcription factor that has a key role in various physiological processes, including the immune response, cell proliferation and growth, synaptic plasticity and cell survival. NF-κB activation may also be associated with neuroinflammation and cognitive impairment, particularly in the context of surgery and anesthesia. Surgical procedures and anesthetic exposure trigger the release of endogenous factors such as high mobility group box 1 and TNF-α, which activate NF-κB translocation into the nucleus. This activation promotes the transcription of target genes, leading to the release of inflammatory mediators and inducing a neuroinflammatory response (149,150). Additionally, key contributors to neuroinflammation, including neutrophils, macrophages, T cells and glial cells, further amplify this inflammatory cascade via NF-κB signaling (149). Notably, activation of the NF-κB signaling pathway has been observed in various animal models of POD, reinforcing its role in postoperative neuroinflammation. Liu et al (151) observed a marked increase in p-NF-κB and p65 levels following exploratory laparotomy in mice, which was accompanied by a reduction in the BBB-associated proteins, zonula occludens protein-1, occludin and claudin-5, in the hippocampus. These findings indicate that NF-κB activation compromises BBB integrity, thereby contributing to POD pathogenesis. NF-κB activation is also associated with various forms of neuronal death. Li et al (152) and Wang et al (153) demonstrated that surgery and anesthesia induce neuronal apoptosis via NF-κB signaling activation, while Dai et al (154) reported that repeated sevoflurane exposure in neonatal mice leads to NF-κB-mediated neuronal pyroptosis. This process disrupts neuronal architecture and connectivity, ultimately impairing cognitive function. Given its key role in neuroinflammation and neuronal damage, targeting NF-κB signaling inhibition may serve as a promising therapeutic approach for POD treatment (155,156).

In addition to the aforementioned pathways, several other signaling cascades have been implicated in the pathogenesis of POD, including the NLRP3 inflammasome, JAK/STAT, Notch and AMP-activated protein kinase pathways (157). Rather than acting in isolation, these pathways engage in extensive crosstalk and dynamic interactions, collectively shaping the onset and progression of POD. For instance, activation of the Wnt/β-catenin pathway enhances PI3K/AKT signaling, which in turn upregulates the BDNF/TrkB pathway which is key for promoting neuronal survival, synaptic plasticity and overall neuroprotection (158). Conversely, pro-inflammatory signaling routes such as TLR and NF-κB may antagonize these protective mechanisms. TLR activation facilitates NF-κB nuclear translocation and the induction of pro-inflammatory cytokines, thereby compromising BBB integrity and suppressing the BDNF expression levels, both of which impair synaptic function (159). Moreover, dysregulated PI3K/AKT signaling may further amplify NF-κB activity, while NF-κB can also be activated downstream of MAPK signaling, establishing a positive feedback loop that exacerbates neuroinflammation (160). These antagonistic interactions between neuroprotective and inflammatory pathways reflect a dynamic imbalance in signal transduction, which may underlie the molecular pathology of POD. A deeper understanding of the interactions among these signaling pathways may provide a theoretical basis for elucidating the molecular mechanisms of POD and for developing multi-target therapeutic strategies.