Piezo1 in microglial cells: Implications for neuroinflammation and tumorigenesis

ABSTRACT

Microglia, the central nervous system (CNS) resident immune cells, are pivotal in regulating neurodevelopment, maintaining neural homeostasis, and mediating neuroinflammatory responses. Recent research has highlighted the importance of mechanotransduction, the process by which cells convert mechanical stimuli into biochemical signals, in regulating microglial activity. Among the various mechanosensitive channels, Piezo1 has emerged as a key player in microglia, influencing their behavior under both physiological and pathological conditions. This review focuses on the expression and role of Piezo1 in microglial cells, particularly in the context of neuroinflammation and tumorigenesis. We explore how Piezo1 mediates microglial responses to mechanical changes within the CNS, such as alterations in tissue stiffness and fluid shear stress, which are common in conditions like multiple sclerosis, Alzheimer’s disease, cerebral ischemia, and gliomas. The review also discusses the potential of targeting Piezo1 for therapeutic intervention, given its involvement in the modulation of microglial activity and its impact on disease progression. This review integrates findings from recent studies to provide a comprehensive overview of Piezo1’s mechanistic pathways in microglial function. These insights illuminate new possibilities for developing targeted therapies addressing CNS disorders with neuroinflammation and pathological tissue mechanics.

Introduction

Microglia, tissue-resident macrophage-like innate immune cells of the central nervous system (CNS), are essential regulators in shaping neurodevelopment, maintaining neural homeostasis, and mediating neuroinflammatory processes and constitute 10% of all cells in the brain [1,2]. Recently, microglia became the center of neuroimmunology research because genome-wide association studies and single-cell sequencing revealed that numerous risk genes for CNS diseases are expressed by microglia [3,4]. In the healthy brain, microglia demonstrate a “ramified” morphology featuring a small cell body with long, thin, and highly branch processes [5,6]. During pathological states, these cells undergo significant morphological changes marked by altered biomechanical properties [5,6]. In addition, phagocytically active microglia undergo a series of complex mechanical motions, such as twisting, ratcheting, rotating, bending, and expanding, to mediate neuronal signaling cascades and intercellular crosstalk [7]. All these suggest that mechanotransduction, the process by which cells convert mechanical stimuli into biochemical signals, plays an important role in regulating microglial activity.

Piezo1, a novel mechanosensitive nonselective cation channel first identified in neuroblastoma cells by Coste and colleagues [8], has been identified as a critical regulator in neurotumorigenesis and neuroinflammation. This exploration is driven by the fact that both pathological processes involve dramatic shifts in mechanical microenvironmental cues, including cellular solid/fluid stress and tissue stiffness alterations [9,10]. The mechanical environment of the brain, characterized by shear stress, tissue stiffness, and cellular deformation, presents a unique set of challenges and stimuli for microglia [11,12]. Piezo1, by virtue of its mechanosensing capabilities, is well-suited to mediate the effects of these forces on microglial behavior. Emerging evidence suggests that Piezo1 activation in microglia can modulate their inflammatory responses, potentially linking mechanical forces to neuroinflammation [13,14]. Furthermore, given the altered mechanical properties of the tumor microenvironment, Piezo1 May also play a role in the crosstalk between microglia and tumor cells, thereby contributing to brain tumorigenesis [15,16].

This review aims to explore the current understanding of Piezo1 in microglial cells, with a specific focus on its role in neuroinflammation and tumorigenesis. By integrating insights from both the broader immune system and CNS-specific studies, we seek to elucidate the mechanisms by which Piezo1 influences microglial function under mechanical stress, and how this contributes to the pathogenesis of neuroinflammation and brain tumors.

Structure, mechanical gating, and biophysical foundations of Piezo1 channel

Piezo1 channel is a homotrimeric mechanosensitive cation channel, and Cryo-electron microscopy reveal that each subunit comprises 38 transmembrane helices, organized into a curved three-bladed helical propeller architecture featuring a central pore and three directly connected peripheral beam-like domains [17,18]. A schematic representation highlights key features: the extracellular cap domain, the central ion-conducting pore, and the beam-like peripheral regions implicated in membrane tension sensing (Figure 1(a)). Piezo1 activation relies on mechanical force transduction through two primary mechanisms: (1) membrane curvature changes induce lateral tension or bending, which directly triggers pore opening [19,20]; and (2) extracellular matrix (ECM) or cytoskeletal forces physically deform the peripheral helical structures of the Piezo1 channel [21]. A defining biological feature of Piezo1 is its rapid inactivation kinetics following channel opening, characterized by an inactivation time constant of about 15 ms at −80 mV [8,22]. To mechanistically interpret these gating dynamics, Gottlieb et al. proposed a linear three-state model involving sequential transitions between closed, open, and inactivated conformations [23], and this kinetic adaptation is critical for filtering sustained mechanical stimuli.

Figure 1.

Schematic illustration of Piezo1 channel structure and physiological function (the figure is created with Figdraw).

The gating behavior of Piezo1 is also modulated pharmacologically. Yoda1, the first identified specific agonist of Piezo1, binds to a hydrophobic pocket about 40 Å of the central pore and stabilizes the open conformation through a wedge-like mechanism that promotes force-induced protein motion, thereby reducing the mechanical threshold required for channel activation [24,25]. Another Piezo1 agonists Jedi1/2 activate the channel by targeting a distinct binding site – the extracellular side of its three-bladed propeller-like architecture – unlike Yoda1, thereby allosterically promoting channel opening through blade deformation rather than direct pore modulation [26]. The most commonly used inhibitors of Piezo1 channels include Ruthenium Red, Gadolinium, and Grammostola spatulata Mechanotoxin 4 (GsMTx4). Ruthenium Red and Gadolinium are nonspecific cation channel blockers that suppress Piezo1 activity by blocking Ca^{2 +} influx [27]. In contrast, GsMTx4—a semi-selective peptide containing six positively charged lysine residues – inhibits mechanosensitive ion channels like Piezo1 by altering membrane tension distribution rather than directly occluding the pore [27,28].

Piezo1 functions as a nonselective cation channel, permeable to both monovalent (K⁺, Na⁺, Cs⁺) and divalent cations (Ba^{2 +}, Ca^{2 +}, Mg^{2 +}). Electrophysiological studies reveal the following permeability sequence under physiological conditions: Ca²⁺ > K⁺ > Na⁺ > Mg²⁺ [8,22]. Mechanically evoked Ca^{2 +} influx through Piezo1 regulates diverse physiological processes in humans: (1) shear stress-induced vasodilation (vasculature) [29]; (2) controlling volume adaptation of erythrocytes [30]; (3) modulating osmosensing in renal tubules [31]; (4) coordinating stem cell proliferation and peristalsis in the intestine [32]; (5) driving mechanoadaptive remodeling in bone [33]; (6) synaptic plasticity modulation [34]; (7) stretch in alveoli [35]; (8) tactile signal transduction [36] (Figure 1(b)).

Expression of Piezo1 in microglial cells

Microglia are derived from embryonic precursors in a colony-stimulating factor 1 receptor-dependent manner, and they can maintain themselves independently of blood monocytes through in situ self-renewal [37,38]. These cells exhibit highly specialized gene expression profiles that are highly heterogeneous due to their location in the CNS and the age and sex of the organism [39–41]. Microglia exhibit heightened sensitivity to environmental mechanical cues, and similar with other types of macrophages, they show a preference for migration to harder regions [42]. Furthermore, these cells dynamically remodel their morphology in response to the stiffness of their surroundings, a plasticity that enables the establishment of region-specific structural and functional adaptations across distinct brain regions [43,44]. This mechanoadaptive capacity underpins their diverse roles in both homeostasis and neurological disorders.

The expression level of Piezo1 is higher than other established mechanosensitive ion channels in microglia [45], and microglia has the highest expression of Piezo1 in the brain compared to other cell types [46]. In general, increased matrix stiffness leads to decreased microglial migration and increased proinflammatory cytokines production, and these effects are attenuated in Piezo1 knockout microglia, which revealed an important role for Piezo1 in microglial migration patterns and immune response [45,47]. In addition, Piezo1 is involved in the polarization of the pro-inflammatory phenotype of microglia, which may be related to Piezo1 channel-mediated Ca2 + influx and crosstalk between cytoskeletal proteins and integrins, and is supported by the upregulation of Piezo1 expression in microglia during inflammation [14,48,49].

The high expression of Piezo1 in bone marrow-derived macrophages underscores its potential as a universal mechanoregulator across tissue-resident macrophage populations, including microglia in the central nervous system. Emerging evidence highlights its functional versatility: for instance, in lung macrophages, cyclic hydrostatic pressure amplifies pro-inflammatory responses via Piezo1-mediated activation of the JUN proto-oncogene and endothelin-1 upregulation [50]. Notably, analogous biomechanical cues may govern microglial heterogeneity. Regional variations in cerebrospinal fluid flow velocity generate spatially distinct fluid shear stress patterns across the brain parenchyma [51], a phenomenon that could drive Piezo1-dependent polarization states in microglia. In addition, microglia utilize adenosine 5′-triphosphate (ATP) as a critical signaling molecule to detect neuronal activity and orchestrate behavioral responses [52]. Neuronal-derived ATP is processed by microglia into adenosine, which suppresses neuronal excitability via adenosine receptors [52,53]. Concurrently, microglial chemotaxis and actin polymerization genes are upregulated during this metabolic cascade, facilitating enhanced cellular deformation and motility – a process central to their surveillance and immune functions [54]. Notably, Piezo1, a mechanosensitive ion channel, has emerged as a regulator of ATP dynamics: Chi et al. demonstrated that astrocytic Piezo1 modulates adult neurogenesis and cognition by governing Ca^{2 +} signaling and ATP release [55]. These findings suggest that Piezo1 May coordinate both exogenous (neuronal/astrocytic) and endogenous ATP levels to fine-tune damage-associated molecular pathways.

Microglial Piezo1 impacts brain tumor progression

Tumor development and invasiveness are closely related to the alteration of mechanical forces, such as the increased solid stress of solid tumors and fluid shear stress [56]. Currently, the exploration of Piezo1 and CNS tumors is mainly about glioma, a primary malignant brain tumor (Table 1, Figure 2).

Table 1.

The role of Piezo1 in neuroinflammation and tumorigenesis.

CNS Diseases	Key Findings	Potential Mechanisms	Therapeutic Implications	References
Glioma	- Piezo1$\uparrow$ in glioma - Piezo1$\uparrow$leads to high tumor malignancy peritumoral brain edema poor prognosis	-Activates integrin-FAK/YAP-TAZ$\to$ $\to$ ECM remodeling, tumor proliferation -Regulates calcium-activated potassium channels $\to$ migration, invasiveness -Mediates transformation of glioblastoma cells into GSCs via Piezo1/Akt signaling axis	−Piezo1 activators enhance GBM treatment regimens -Induce anti-tumor microglial activity	[16,57,58,63–66]
Cerebral Ischemia Ischemia/Reperfusion Injuries	-Piezo1$\uparrow$ $\to$$\uparrow$ recovery in ischemic stroke -Piezo1$\downarrow$$\to$$\downarrow$ infarct size in ischemic stroke	-Angiogenesis via Ca2±dependent CaMKII/ETS1 - Activated HIF1α/ferroptosis axis in ischemic injury	- Potential anti-thrombotic therapy	[86,88–90]
AD	-Piezo1$\uparrow$ with age, affecting mechanical sensitivity -Piezo1$\uparrow$$\to$$\downarrow$ Aβ burden and cognitive impairment −Alter gene expression of cytoskeletal dynamics and synaptic organization	-ECM stiffness sensing $\to$ microglial migration to Aβ plaques -Ca2 + influx $\to$ phagocytosis, microglial survival -Lipid imbalance alters Piezo1 function, affecting microglial activity	-Piezo1 activators reduce Aβ burden −Transcranial magnetic stimulation and dietary fatty acids for microglial function	[45,47,94–98,101]
MS	-brain parenchymal stiffness $\downarrow$ -Piezo1$\downarrow$$\to$$\downarrow$ demyelination; neuronal damage	-Senses changes in brain parenchymal stiffness-Enhances phagocytosis via CaMKII-Mst1/2-Rac -Regulates oligodendrocyte proliferation and axon remyelination via Ca2+/CaMKII/NOS	−Piezo1 inhibitors for neurodegeneration and remyelination	[75–78,80,81]

AD, Alzheimer’s Disease; MS, Multiple Sclerosis; NOS, nitric oxide synthase.

Figure 2.

Schematic illustration of the potential mechanisms of Piezo1 channel in CNS tumor and neuroinflammatory.

Microglial Piezo1 and glioma

Piezo1 is overexpressed in glioma cells, where it responds to the increased mechanical stiffness of the tumor microenvironment and the levels of its expression correlates with tumor malignancy and poor prognosis [57,58]. Glioblastoma (GBMs), as the most malignant glioma, is characterized by tumor-associated microglial and macrophage infiltration exceeding 30% of the total infiltrating cells in the tumor microenvironment [59].

As for the possible mechanism of Piezo1 in glioma, Chen et al and Zhou et al proposed that the activation of Piezo1 promotes calcium influx, which in turn activates downstream integrin-focal adhesion kinase pathway and the Yes-associated protein/TAZ transcriptional coactivators, and these pathways promote ECM remodeling, tumor cell adhesion, and proliferation, further exacerbating glioma malignancy [15,60]. Piezo1 under hypotonic-induced cell swelling controls regulatory volume reduction in human glioblastoma cells by regulating calcium-activated potassium channels, thereby participating in tumor cell migration and invasiveness [61], and Qu et al. also demonstrated that Piezo1 overexpression is correlated with the degree of peritumoral brain edema in GBMs [16]. In recent years, with the concept of glioma stem cells (GSCs) proposed, researchers have also realized that GSCs have become one of the important reasons for treatment resistance due to their strong self-renewal and cell differentiation ability [62]. Luu et al found that Piezo1 mediated the transformation of glioblastoma cells into GSCs and the formation of unique spatial distribution of GSCs in the tumor microenvironment, and specific circular RNAs in glioma stem cell-derived exosomes regulate tumor cell proliferation and migration in vitro by affecting the Piezo1/Akt signaling axis, and which provided a potential therapeutic target [63,64]. Sonodynamic therapy for the treatment of invasive tumors induces glioma cell death through the activation of the Piezo1/Ca2+/lipid peroxidation pathway, while activating the pro-inflammatory phenotype of microglia, which play anti-tumor role in the glioma [65]. In addition, Piezo1 could also enhance the effects of two other treatments for GBMs: temozolomide and tumor necrosis factor-related apoptosis-inducing ligand. Knoblauch et al. investigated that supplementation of Yoda1, a Piezo1 activator, to the above two therapeutic agents may sensitize GBM cells to tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis and overcome temozolomide resistance, which also provides a targeted, minimally invasive therapeutic approach [66]. It is important to emphasize that these effects of Piezo1 were detected in glioma cell lines and need to be further validated in microglia.

Microglial Piezo1 and other CNS tumors

Although an adequate association has been established between Piezo1 and solid tumors characterized by changes in ECM structure and stiffness [67], it has not been reported in tumors other than gliomas in the CNS [7].

Given Piezo1’s ability to enhance the movement and migration of tumor cells, as well as its role in preserving the integrity of the blood-brain barrier by suppressing the activation of the NLRP3 inflammasome [68], there may be a potential link between Piezo1 and the occurrence of metastatic brain tumors. Although Piezo1 is not yet implicated, another mechanosensing channel of this family, Piezo2 has been found to contribute to Sox2+ tumor cell behavior. In the context of medulloblastoma, Sox2+ tumor cells are regarded as tumor stem cells that are capable of propelling tumor growth and relapse. These cells exhibit a unique Piezo2-dependent behavior: their cellular processes actively envelop blood vessels to form a blood-tumor barrier, and this barrier critically limits chemotherapeutic drug penetration into brain tissue [69]. Importantly, experimental ablation of the mechanosensitive ion channel Piezo2 disrupts blood–tumor barrier formation [69], suggesting that mechanical sensing pathways may regulate childhood brain tumor-protective structure.

Medulloblastoma is the most prevalent malignant pediatric brain tumor. When considering other CNS pathologies in pediatric patients, Piezo1 has been found to contribute to hypoxic-ischemic encephalopathy in neonates through GPX4-dependent ferroptosis [70], suggesting druggable potential of ECM-Piezo1 signaling to ameliorate neurological outcomes. Furthermore, another mechanosensitive channel TMEM63A-mediated Ca^{2 +} influx is necessary for normal myelination process in infancy [71]. Although direct evidence in medulloblastoma remains limited, these parallel findings across pediatric CNS disorders suggest that mechanotransduction mechanisms may represent a broader class of therapeutic targets worthy of systematic investigation for childhood brain tumors or neurodevelopmental diseases.

Microglial Piezo1 impacts neuroinflammation

Neuroinflammation is an inflammatory process that occurs within the CNS, usually in response to a variety of neurological injuries, such as infection, ischemia, trauma, or neurodegenerative diseases. Neuroinflammation involves the activation of immune cells in the central nervous system, particularly microglia, so we focused on the role of Piezo1 in CNS disease-associated neuroinflammation (Table 1, Figure 1).

Microglial Piezo1 and multiple sclerosis (MS)

MS is a chronic inflammatory disease characterized by demyelination and axon degeneration. While the exact etiology of MS remains unclear, extensive research has highlighted the crucial role of both peripheral and CNS-resident immune cells in its pathology [72–74]: initially, peripheral leukocytes attack the CNS, damaging oligodendrocytes and myelin; as the disease advances, microglia and astrocytes drive inflammation by releasing pro-inflammatory cytokines, leading to severe demyelination, neurodegeneration, and disrupted nerve transmission, which result in various motor and non-motor symptoms.

Significant decrease in brain parenchymal stiffness was observed in relapsing-remitting MS, chronic-progressive MS and clinically isolated syndrome [75,76], and it is demonstrated that the pharmacological inhibition of Piezo1 prevents demyelination and neuronal damage in an organotypic cerebellar slice culture [77]. Macrophage Piezo1 mediates stiffness-dependent F-actin remodeling and amplifies neuroinflammation via Calcium-calmodulin-dependent protein kinase II (CaMKII)-Mst1/2-Rac/ROS-driven phagocytosis [78]. Myelination by oligodendrocytes is essential for CNS function [79]. However, emerging evidence suggests that activation of the mechanosensitive channel Piezo1 exerts dual inhibitory effects: it suppresses oligodendrocyte proliferation/migration and restricts axon regeneration via Ca^{2 +}/CaMKII/nitric oxide synthase/cGMP-dependent pathway, ultimately impairing remyelination efficiency in both in vitro and in vivo models [80,81].

The dynamic interactions between T cells, B cells, and CNS-resident glial cells (such as microglia and astrocytes) serve as key initiators and drivers of neurodegeneration in MS [82]. Critically, mechanosensitive signaling in T cells may amplify this pathogenic cascade. As demonstrated by Liu et al., Piezo1 in CD4+ T cells enhanced T cell receptor signaling through the Ca^{2 +}/calpain axis [83], and thus targeting Piezo1 in T cells may enable immunoregulation of MS to suppress pathological hyperactivation. In vitro studies demonstrate that microglial Piezo1 inhibition under high-glucose conditions activates c-Jun-N-terminal kinase 1/mechanistic target of rapamycin phosphorylation [84], thereby mitigating inflammation-induced damage. Nevertheless, the pathophysiological relevance of microglial Piezo1 in MS remains to be fully characterized in vivo.

Microglial Piezo1 and neuroinflammation in cerebral ischemia and ischemia/reperfusion injuries

Cerebral ischemia results from an obstruction in the cerebral vasculature, initiating a series of pathological events. Initially, vascular or hematological abnormalities lead to the decrease of regional cerebral blood flow; this ischemic episode triggers the release of chemical mediators that precipitate cell necrosis, and the subsequent reperfusion can exacerbate the injury, potentially leading to complications such as the disruption of the blood-brain barrier and hemorrhagic transformation [34,85].

Piezo1 mRNA levels in red blood cells have been shown to be positively correlated with the recovery degree of ischemic stroke [86], which have linked Piezo1 protein to cerebral ischemia. Li et al. reported that cardiomyocyte Piezo1 interacted with Caspase-8 to exacerbate cardiac ischemia-reperfusion injury [87], and Xie et al. found that macrophage Piezo1 was involved in the angiogenic response following hindlimb ischemia via Ca2+ dependent CaMKII/ETS proto-oncogene 1 signaling, and the deletion of Piezo1 could promote perfusion recovery after hindlimb ischemia [88], which suggested a possible mechanism for the association of macrophages with cerebral ischemia. While Guo et al. proposed that alterations in cerebral blood flow or vasogenic edema may activate the Piezo1/HIF1α/ferroptosis axis to mediate cerebral ischemic injury – a hypothesis extrapolated from mechanistic parallels in other diseases and lacking direct experimental validation [89] —subsequent experimental evidence in neonatal hypoxic-ischemic encephalopathy demonstrated that ECM remodeling-induced Piezo1 activation directly triggered ferroptosis through a GPX4-dependent pathway [70]. These findings collectively suggest that Piezo1-driven ferroptosis may operate through divergent mechanisms across distinct pathological contexts, urging targeted studies to unravel its precise role in specific cerebrovascular disorders. The hemodynamic abnormalities in hypertensive patients affect platelet function and accelerate thrombosis, so hypertension is one of the high-risk factors for ischemic stroke. A recent study demonstrated that the pharmacological inhibition of Piezo1 effectively reduced arterial thrombosis and reduced infarct size in ischemic stroke [90], which provided a new strategy for antithrombotic therapy.

Microglial Piezo1 and neuroinflammation for Alzheimer’s disease (AD)

AD is a neurodegenerative disease characterized by the formation of high-hardness amyloid-beta (Aβ) plaques, and neuroinflammation, a central mechanism of AD, is closely related to the development of AD [91]. Activated microglia in the AD brain tightly wrap Aβ plaques, and their long-term activation can lead to reactive microgliosis, creating a vicious cycle that accelerates neurodegeneration [92,93]: while neuroinflammation initially serves as a protective mechanism to clear debris and pathogens, its chronic activation in AD contributes to synaptic dysfunction, neuronal loss, and cognitive decline.

The local increase of Piezo1 expression with age and the change of ECM stiffness gradient during aging can affect neural mechanical sensitivity [94,95], which may partly explain that AD is a progressive age-related disease. Microglial Piezo1 deletion affects microglial gene expression, particularly genes related to cytoskeletal dynamics, synaptic organization, cell-matrix adhesion, and endocytosis. Microglia Piezo1 can migrate to the lesion site by sensing the change of the stiffness of the Aβ plaques, and Piezo1 mediated microglial phagocytosis, and the compacting of Aβ plaque by activating Ca2+ influx [45,47,96]; Similarly, the activation of Piezo1 enhanced the survival and phagocytic activity of human induced pluripotent stem cell-derived microglial-like cells, thereby clearing Aβ accumulation [97]. In summary, the pharmacological activation of Piezo1 alleviates Aβ burden and cognitive impairment, suggesting that pharmacological intervention of Piezo1 signaling may have therapeutic potential for AD. In addition, a transcranial magnetic acoustic stimulation system based on transcranial ultrasound stimulation in magnetic field enhanced autophagy by activating microglia Piezo1, promoted the phagocytosis and degradation of Aβ, and alleviates neuroinflammation and synaptic plasticity damage in vivo [98].

Dietary fatty acids, a novel class of microglial regulators, not only cross the blood-brain barrier to modulate CNS function [99,100] but may also directly influence Piezo1 activity through lipid bilayer remodeling [101]. Mechanistically, fatty acids dynamically alter membrane thickness and fluidity, physical properties known to govern the mechanosensitivity and gating kinetics of Piezo1 channels [101]. This lipid-Piezo1 interplay holds particular relevance in AD, where pathological lipid imbalances – such as decreased phosphatidylcholines, sphingomyelins, and phospholipids – correlate with aggravated neuropathology and cognitive performance [102]. Notably, such lipid disturbances could compromise Piezo1-mediated mechanotransduction in microglia, potentially explaining observations that fish oil supplementation (rich in long-chain polyunsaturated fatty acids) enhances microglial plaque clearance and reduces neuritic dystrophy [103]. Importantly, epidemiological studies associate high dietary intake of long-chain polyunsaturated fatty acids with reduced AD risk [104], suggesting that lipid-driven Piezo1 modulation may represent a previously overlooked therapeutic axis in neurodegeneration.

Conclusions

Piezo1 translates tissue-scale mechanical perturbations into a microglial polarization program that exacerbates neuroinflammation or suppresses antitumor immunity. The dual nature of Piezo1—both as a neuroinflammatory amplifier in demyelinating disease and as an immune checkpoint in glioma – reveals the importance of mechano-immune regulation in CNS diseases. Future studies must decode how Piezo1 cooperates with other types of mechanosensitive ion channels to form adaptive mechanosignaling networks, while exploring the regulatory mechanisms of microglial mechanoresponses. By linking mechanobiology to neuroimmunology, recalibration of microglial mechanosensing is used to open up new therapeutic avenues.

Abbreviations

CNS

central nervous system

ATP

Adenosine 5’ triphosphate

GBMs

Glioblastoma

ECM

extracellular matrix

GSCs

glioma stem cells

MS

multiple sclerosis

CaMKII

Calcium-calmodulin-dependent protein kinase II

AD

Alzheimer’s disease

Aβ

amyloid-beta

Funding Statement

Construction Plan of National Key Clinical Specialty Projects in 2023.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Authors’ contributions

Bo Yang: Conceptualization, conducted the literature search, writing, original manuscript preparation; Zhenyu Li: Conceptualization, conducted the literature search, writing; Peiliang Li and Yuhan Liu: conducted the literature search, revised the final version; Xinghuan Ding: supervised the project and interpreted the data; Enshan Feng: Conceptualization, supervised the project, revised the final version, funding. All the authors read and approved the final manuscript.

Consent for publication

All authors concur with publishing the study at the present version. The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Data availability statement

No datasets were generated or analyzed during the current study.