T cells are central to adaptive immunity, and continuously sense, generate, and respond to mechanical forces. Advances in mechanoimmunology show that T-cell behavior is tightly shaped by the physical properties of their environment, including stiffness, viscoelasticity, ligand arrangement, and tissue topography. T-cell activation depends not only on biochemical signals but also on forces transmitted through the T-cell receptor, coreceptors, and mechanosensitive ion channels, which converge on the cytoskeleton to regulate signaling and effector function. When these mechanical interactions are disrupted, as in cancer, autoimmune diseases, or aging, T-cell function is impaired. Despite recent progress, T-cell mechanobiology remains partially understood, limited by challenges in measuring forces at relevant spatial and temporal scales. Incorporating biophysical principles into the design of immunotherapies may enhance treatment efficacy, specificity, and safety. This review summarizes emerging concepts in T-cell mechanobiology and outlines key challenges and future directions toward integrating mechanical and biochemical regulation of adaptive immunity.

Pathological scarring following skin trauma remains a formidable clinical challenge. Hydrogel dressings can promote wound closure by providing wet healing environment, yet the role of the dressing's mechanical microenvironment on the scar formation is overlooked. Herein, a series of mechanically-tunable hydrogels were produced from the same concentrations of polyvinyl alcohol (PVA) and poly(polyethylene glycol methacrylate-co-glycidyl methacrylate) (PPG) without or with the addition of hyperbranched poly-l-lysine (HBPL) via a cyclic freeze-thaw method. All the hydrogels could maintain their mechanical strength under physiological conditions. Culture with fibroblasts on the hydrogels in vitro showed that the high-stiffness environment triggered the Piezo1 ion channel (the mechanosensitive ion channel), inducing a calcium influx, conveying severe scarring potential. The low-modulus hydrogels (∼20-29 kPa) significantly reduced scar elevation index, α-smooth muscle actin expression and collagen I/III ratios in a rabbit ear ventral full-thickness wound model in vivo. While the mechanical modulus of the hydrogel played a dominant role in scar suppression, the incorporation of HBPL provided a modest yet synergistic anti‑scarring benefit by effectively adsorbing key inflammatory factors. The material system demonstrated its great potential as a ready-to-use wound dressing for clinical translation. By identifying a mechanical adaptive window for wound dressings, this study provides a framework for the rational design of mechanotherapeutic biomaterials to achieve better scar-less tissue regeneration. STATEMENT OF SIGNIFICANCE: Pathological scarring following skin trauma remains a formidable clinical challenge. Hydrogel dressings can promote wound closure by providing a wet healing environment, yet the role of the dressing's mechanical microenvironment on the scar formation is overlooked. Herein, mechanically-tunable polyvinyl alcohol-based hydrogels with the same chemical compositions were prepared via a cyclic freeze-thaw method. The substrate stiffness modulated the Piezo1 mechanosensitive axis, triggering a stiffness-dependent calcium influx. The low-modulus dressings effectively suppressed pathological hyperplasia with the smallest scar elevation index, downregulated α-smooth muscle actin expression, and a transition toward a regenerative type III/I collagen ratio. By silencing the Piezo1-mediated mechanotransduction pathway through a low-modulus interface, this study provides a robust material design framework that optimizes the regenerative microenvironment, offering a promising dual-strategy approach for clinical wound management and the prevention of pathological fibrosis.

Astrocytes are the most abundant glial cells within the central nervous system. They are highly specialized mechanosensors able to detect the kinetics and magnitude of external biomechanical stimuli (i.e., matrix substrate stiffness and shear/compressive/tensile biomechanical strains). They integrate these biomechanical cues through a complex interplay of integrins, focal adhesions, junctional proteins and mechanosensitive channels. In development, this crosstalk secures astrocyte fate maturation and heterogeneity. However, in mechanically induced neural injuries, these mechanosensing elements can drive aberrant signaling. The range of astrocyte mechanoresponses in pathology include cytoskeletal remodeling that impacts cellular morphology and stiffness, disrupted calcium signaling, altered metabolism, pro-inflammatory signaling, and disruptive matrix remodeling. Ultimately, these mechanoresponses can form positive feedback loops that aggravate reactive astrogliosis, damage neural tissue, and altogether inhibit neural regeneration in these diseases. This review synthesizes the current knowledge of astrocyte mechanobiology during development and disease, and highlights the importance of continued investigation into the therapeutic potential of mitigating astrocyte mechanodysfunction in disease.

Evaluation of a stable non-aqueous coupling medium for transcranial ultrasonic stimulation and sonogenetics.

The mechanosensitive ion channel Piezo1 promotes colitis by modulating oxidative stress and ferroptosis-related markers.

Exercise training is a vital component of rehabilitation for individuals with spinal cord injury (SCI). However, its mechanisms of action remain unclear, which severely limits the development and implementation of precise exercise prescriptions for SCI. In this article, we propose a core hypothesis: mechanical stimulation generated by exercise is converted into key biological signals that regulate SCI repair through the activation of mechanosensitive channels (MSCs). To test this hypothesis, we adopt a narrative review approach to systematically integrate current evidence on MSCs including Piezo1, TRAAK/TREK-1, and TRPC1 in the contexts of neuroplasticity, bone and muscle homeostasis, and inflammatory responses. Based on this evidence, we construct a mechanistic framework linking specific MSCs to exercise-induced functional benefits, revealing the potential molecular logic by which exercise promotes spinal cord injury repair. As a hypothesis-driven narrative review, this article not only provides a theoretical foundation for developing quantifiable, personalized exercise prescriptions for SCI rehabilitation, but also outlines several testable research directions to facilitate experimental validation and clinical translation of the proposed hypothesis.

Respiratory pathogens, such as Pseudomonas aeruginosa damage the alveolar-capillary barrier leading to lung injury and stiffness. Lung stiffness is a key macrophage signal for bacterial clearance, but it remains unknown how stiffness-sensing mechanosensitive ion channels in macrophages are regulated during pneumonia. Macrophage Piezo1 is critical to bacterial clearance in experimental pneumonia in vivo; however, identification of putative matrix-derived signals and the mechanism of their effects remain to be determined. We investigated the role of P. aeruginosa virulence factors on Piezo1 activity in macrophages on infected lung matrix stiffness. Using bone-marrow derived macrophages, we measured Piezo1 abundance and function and bacterial clearance in response to P. aeruginosa virulence factors on pathophysiologic range lung stiffnesses and standard tissue culture conditions. To our knowledge, our work is the first to show that during pneumonia, transcription of the mechanosensitive ion channel Piezo1 is increased in macrophages by the NF-κB transcription factor, p65, through its signaling adaptor protein, MyD88, leading to increased Piezo1 Ca2 + channel activity. Piezo1 mRNA abundance is increased in association with open chromatin at the Piezo1 promoter in macrophages. The enhanced level of Piezo1 increases the abundance of transcription factor EB (Tfeb) resulting in lysosome biogenesis and stiffness-dependent phagolysosome maturation, a critical step for macrophage bacterial clearance. Our data support the mechanism whereby transcription of macrophage Piezo1 is enhanced by p65 to augment bacterial clearance on an injured, stiffened lung matrix during pneumonia. Therefore, Piezo1 is a future therapeutic target against pneumonia-induced lung injury.

By elucidating how nematode-derived signals drive trap formation and activation, this work uncovers a new mechanotransduction pathway in nematode-trapping fungi (NTF) and expands the known roles of mechanosensitive ion channels of small conductance-like channels (MSL) beyond osmotic regulation, providing the first molecular insight into mechanosensitive channel-driven regulation of predatory behavior in filamentous fungi and offering new insights for developing biological control strategies against plant-parasitic nematodes.

Studies on the mechanosensitive ion channel Piezo2 largely focus on its role in the peripheral nervous system, particularly in touch and pain sensation. Here, we investigate Piezo2 function in the anterior visual pathway of the central nervous system with a focus on oligodendrocyte (OL) biology and myelin integrity. Using single-nucleus RNA sequencing, we identify Piezo2 expression in late differentiated OLs of the murine optic nerve, with minor expression in retinal ganglion cells. OL-specific Piezo2 deficiency results in age-dependent motor impairment and selective disruption of myelin compaction in small-caliber optic nerve axons, a fiber population known to be particularly vulnerable in demyelinating disease. Differential gene expression analysis further indicates that Piezo2 regulates myelin compaction and white matter integrity in mature OLs. Consistent with these findings, OL-encoded PIEZO2 expression is reduced in optic nerve lesion areas from multiple sclerosis patients, highlighting a convergent mechanism of small-caliber fiber vulnerability. Together, these data identify Piezo2 as an age-related regulator of OL function and myelin integrity, with potential relevance for preserving white matter structure in multiple sclerosis.

Mechanical sensation has become a recent focus and key pathological driver of cardiac fibrosis. However, the crosstalk between major mechanosensitive cell and fibroblasts remains to be elucidated. In this study, single-cell temporal atlas of mechanosensitive ion channels is depicted in transverse aortic constriction male mouse heart. Piezo1 is the most abundant mechanosensitive ion channel and exhibits the highest expression in epicardial cells. Epicardial-specific Piezo1 knockout mice exhibit decreased fibrosis and cardiac dysfunction. Piezo1 mediates epithelial-mesenchymal transition only contributes to subepicardial fibrosis. Further functional experiments and human samples validation reveal that Piezo1 facilitates intraventricular fibroblast activation via the Chemerin-Cmklr1 paracrine signaling pathway. The activation of cardiac fibroblasts is mediated by Pi3k-Akt1-Pou3f1 pathway. The Cmklr1 inhibitor α-NETA effectively mitigates myocardial fibrosis and dysfunction, holding therapeutical potential. Collectively, this study untangles the global landscape of mechanosensitive channels and the spatiotemporal mechanism of epicardial cells to activate fibroblast via the Chemerin-Cmklr1 paracrine signaling pathway.

Liver metastasis remains the primary cause of death in pancreatic cancer. Collagen deposition by activated hepatic stellate cells (HSCs) generates a stiff fibrotic niche that favors metastatic colonization, yet the underlying mechanisms remain incompletely understood. Using stiffness-tunable hydrogels, it is shown that elevated substrate stiffness activates HSCs and establishes a self-reinforcing loop of matrix stiffening. Mechanistically, stiffness triggers Piezo1-mediated Ca2 + influx, induces endoplasmic reticulum stress (ERS), and activates the IRE1α-XBP1 pathway to upregulate glia maturation factor gamma (GMFG) transcription and secretion. GMFG is transported into pancreatic cancer cells where it binds to intracellular tensin-4 (TNS4), promoting FAK/AKT phosphorylation and coordinating two programs critical for metastatic outgrowth: enhanced cell-ECM adhesion and increased de novo fatty acid synthesis. In mice with graded liver stiffness, pharmacological inhibition of mechanosensitive cation channels reduces metastatic burden and dampens GMFG-associated epithelial and lipogenic features, while targeting the GMFG-TNS4 axis suppresses early hepatic micrometastatic seeding and long-term liver metastasis burden. Together, these findings define a mechano-ER stress-paracrine cascade linking fibrotic stiffness to pro-colonization signaling, highlighting the Piezo1-GMFG-TNS4 pathway as a therapeutic vulnerability in PDAC liver metastasis.

The brain's disproportionate energy demand creates an enduring bioenergetic imperative where mitochondrial performance directly determines synaptic resilience and neuronal survival. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) has emerged as a master transcriptional regulator orchestrating mitochondrial biogenesis, antioxidant defenses, proteostasis, and neuroplasticity, with dysregulation of this axis representing a convergent pathogenic mechanism across Parkinson's disease, Alzheimer's disease, Huntington's disease, stroke, and neuropsychiatric disorders. Despite compelling preclinical evidence, conventional pharmacological PGC-1α activators confront fundamental translational barriers including poor blood-brain barrier penetration, inadequate bioavailability, and off-target metabolic effects. This review synthesizes mechanistic evidence suggesting that focused ultrasound may provide a noninvasive platform for regionally precise modulation of PGC-1α pathways. In this review, focused ultrasound is presented as a proposed upstream modulator of the PGC-1α axis. Existing studies support its ability to induce membrane tension, engage mechanosensitive channels such as Piezo1 and TRAAK, and trigger downstream kinase signaling, but the full ultrasound → PPARGC1A → neuroprotection chain in brain tissue remains a working hypothesis rather than a demonstrated therapeutic mechanism. Indirect priming through reversible blood-brain barrier opening, hemodynamic augmentation, and glial immunomodulation may further facilitate this model. We integrate emerging concepts including the mitochondrial synapse, PGC-1α isoform diversity, and theranostic architectures combining functional ultrasound mapping with targeted sonication. By defining mechanistic opportunities, disease-specific therapeutic strategies, and the sonogenetics frontier, this review proposes a hypothesis-generating roadmap for ultrasonic modulation of PGC-1α-dependent neuroprotection, a drug-free, focal approach that converts acoustic energy into a testable mitonuclear rescue framework requiring direct experimental validation.

Glaucoma leads to progressive degeneration of retinal ganglion cells (RGCs), highlighting an urgent need for neuroprotective strategies beyond intraocular pressure reduction. Our previous work demonstrated that activation of the mechanosensitive channel Transient Receptor Potential Vanilloid 4 (TRPV4) contributes to RGC apoptosis in a chronic ocular hypertension (COH) rat model, and that the TRPV4 antagonist HC-067047 exhibits neuroprotective potential. However, its mechanism of action remains unclear, and its therapeutic efficacy is limited by poor RGC targeting, rapid clearance, and associated toxicity. In this study, we developed an RGC-targeted and reactive oxygen species (ROS)-responsive drug delivery system by combining cholera toxin subunit B (CTB)-mediated selective uptake with an ROS-cleavable polymeric shell encapsulating HC-067047. The nanoparticles were efficiently internalized by RGCs and released the drug specifically in the COH-induced high-ROS microenvironment. Mechanistically, COH-induced TRPV4 activation led to calcium dysregulation and impaired autophagic flux-a key process linked to RGC vulnerability. Inhibition of TRPV4 via this targeted delivery system restored autophagic flux and significantly reduced COH-induced RGC injury. These findings identify TRPV4-mediated autophagy dysregulation as a critical mechanism in glaucomatous damage and propose a precise, controlled-release nanotherapeutic strategy for the treatment of glaucoma.

Bioelectric signaling is well characterized in neurons and cardiomyocytes but remains largely unexplored in epithelia. Using multielectrode arrays, we demonstrate that localized laser injury to epithelial monolayers (primary human keratinocytes and MDCK cells) triggers voltage spikes in the range of 4 to 12 per min for over 60 min postinjury. These spikes exhibit depolarization, repolarization, and hyperpolarization phases lasting 1 to 2 s, a timescale three orders of magnitude slower than neuronal action potentials. Spike amplitudes and frequencies detected at 740 μm from the injury site (the maximum distance measured) are comparable to those at 140 μm and exhibit a nonmonotonic spatial profile, arguing against simple radial propagation from the wound. Calcium chelation with ethylenediaminetetraacetic acid abolishes spiking entirely, and inhibition of myosin II with blebbistatin produces equivalent suppression, indicating that calcium influx and actomyosin contractility are both required. The mechanosensitive channel modifier GsMTx4 partially suppresses spiking, implicating the role of stretch-activated ion channels. Most strikingly, pharmacological activation of the mechanosensitive channel TRPV4 and Piezo1 generates high-amplitude spikes (1 to 10 mV) even in the absence of injury, demonstrating that mechanosensitive channel activation is sufficient to drive epithelial electrical excitability. These findings reveal that epithelia, long thought to lack action-potential-like dynamics, possess intrinsic bioelectric excitability gated by mechanical stress, challenging the classical distinction that electrical signaling is exclusive to specialized tissues like neurons and muscles and suggesting a signaling modality for coordinating collective cellular responses across tissue-scale distances.

In this study, scanning ion-conductance microscopy (SICM) is established as a multifunctional nanoscale platform for localized mechanical stimulation, high-resolution topographic imaging, and quantitative mapping of cellular Young's modulus. Using controlled force interactions between a nanopipette tip and the sample, we achieved spatially resolved mechanical activation of primary rat hippocampal neurons and astrocytes. Localized mechanical stimulation of specific subcellular regions induced elevations in intracellular Ca2+ levels, indicating the activation of mechanosensitive ion channels. Concurrent topographic imaging and Young's modulus mapping revealed that mechanical stimulation triggered distinct cytoskeletal remodeling responses. Specifically, stimulation of the neuronal cell body led to a significant increase in Young's modulus (stiffening), whereas dendritic stimulation produced no measurable change. In contrast, astrocytes exhibited bidirectional responses: somatic stimulation decreased Young's modulus (softening), while stimulation of astrocytic processes increased it (stiffening). Inhibition of actin polymerization with cytochalasin D completely abolished all stimulation-induced changes in Young's modulus in both cell types. Collectively, our findings demonstrate that SICM enables direct correlation of applied nanomechanical forces, intracellular calcium dynamics, and real-time alterations in cellular stiffness, thereby offering new insights into compartment-specific mechanotransduction pathways and adaptive cytoskeletal reorganization.

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by pathological features such as chondrocyte loss and cartilage matrix degradation. Superficial zone chondrocytes (SFC), located in the outermost layer of articular cartilage and in direct contact with synovial fluid, are the first to respond to mechanical stress and friction. In this study, SFC were isolated and identified in vitro, and their proliferatives and anti-apoptotic properties were examined. Additionally, an early OA inflammatory environment was successfully simulated in cell experiments, demonstrating that inflammatory conditions reduce stemness-associated marker expression in SFC, activate multiple inflammatory pathways, and promote MMP3 expression. When SFC were subjected to cyclic mechanical stretching under inflammatory conditions, increased expression of the mechanosensitive channel Piezo1, enhanced calcium-associated mechanotransduction sensitivity, and disruption of the cytoskeleton were associated with aggravated catabolic responses and apoptosis under inflammatory mechanical stimulation. These findings elucidate the role of SFC in early OA pathogenesis and provide insight into early OA pathogenesis and suggest potential directions for mechanism-based intervention.

Macrophages play a crucial role in the inflammation and wound repair processes of radiation-induced lung injury (RILI). The mechanosensitive ion channel Piezo1 is upregulated during these inflammatory and wound repair processes. However, the involvement of macrophage Piezo1 in the pathogenesis of RILI remains unclear. This study aims to elucidate the regulatory role of Piezo1 in the injury and repair process in RILI and to investigate the underlying mechanisms. We established Myeloid-specific knockout of Piezo1 (Piezo1∆ LysM) mice, and the mice were subjected to total-chest irradiation (15Gy) to simulate the clinical situation. Additionally, LPS treatment was performed on bone marrow-derived macrophages in vitro. The expression of Piezo1 in RILI was analyzed using the GEO database. In Piezo1fl/fl and Piezo1∆LysM mice, Piezo1 and EMT markers expression were detected by immunofluorescence, RT-qPCR, and Western blotting, the concentration of inflammatory factors by ELISA, alveolar macrophages were sorted by flow cytometry. In vivo and in vitro experiments involving Myeloid Piezo1 knockout and activation of Piezo1 with the specific agonist Yoda1 were conducted to observe the effects on lung injury. Our findings revealed that Piezo1 is upregulated in lung macrophages in mice with RILI. Myeloid Piezo1 knockout provided protective effects in mice with RILI. Myeloid-specific Piezo1 deficiency alleviates inflammatory responses, manifested by the alleviation of inflammatory damage in lung tissue, changes in the concentrations of related inflammatory factors. Simultaneously, this deficiency reduces radiation-induced pulmonary fibrosis, with improved fibrosis indicators and decreased expression of EMT markers. Moreover, myeloid Piezo1 knockout inhibited paracrine-induced EMT of BEAS-2B cells by alveolar macrophages, and reduced macrophage recruitment. Mechanistically, the regulatory effects of Piezo1 on lung macrophages were activated Ca2+-dependent calpain signaling, which critically upregulated MCP-1/CCR2/NF-κB and endoplasmic reticulum (ER) stress-induced ATF6/CHOP signaling axis. Our findings revealed the important function of Piezo1 in RILI, knockout or pharmacological inhibition of Piezo1may serve as a promising strategy for treating RILI.

SummaryMechanical force transduction is essential to survival, underlying biological processes as fundamental as morphogenesis, somatosensation, audition, and interoception; and driving pathologies as diverse as hypertension and cancer metastasis. Exogenous forces are translated to intracellular signals through transient changes in membrane tension which are currently not possible to directly monitorin situ. To remedy this, we have designed and validated Tension TRAAKer, a chemigenetic fluorescent membrane tension reporter for the visualization of tension induction, propagation, and dissipation in living cells. Tension TRAAKer is derived from inserting a tension-sensitive nonconductive variant of the mechanosensitive potassium ion channel TRAAK into a self-labelling HaloTag. Increasing membrane tensions effect conformational changes in the TRAAK channel that are optically monitored by a HaloTag-conjugated fluorogenic (environment-sensitive) dye. EGFP incorporation C-terminal to the HaloTag enables unambiguous tension reporting in mobile membranes via dual-color ratiometric imaging that controls for variations in sensor density. Tension TRAAKer reports membrane tension changes rapidly, reversibly, and with spatiotemporal precision—its fluorescence scaling to both stimulus magnitude and area, with consistent effect sizes observed between diverse cell types. It better distinguishes among elevated membrane tensions than do available indirect chemical reporters, with the additional advantage of being readily genetically targetable. We thus expect Tension TRAAKer to be a powerful tool for the study of membrane tension across biological systems and disease states.

Acoustic modulation of fungal friends and foes.

Tumor cells encounter diverse mechanical forces during cancer progression, and the mechanosensitive ion channel PIEZO1 governs how breast cancer cells adapt to these cues, thereby shaping their metastatic potential. Analysis of clinical datasets revealed differential regulation of PIEZO1 between primary and metastatic breast cancers. Here, we demonstrate that PIEZO1 regulates the proliferation, migration, and survival of breast cancer cells in a mechanosensitive environment-dependent manner. Under static conditions, optimal PIEZO1 activity is required for both proliferation and migration, which is mediated by metalloproteinases, RHOA, and S100A4. While optimal PIEZO1 activity is required for sustained proliferation and migratory capacity, loss of PIEZO1 conferred a survival advantage in triple-negative breast cancer cells under mechanically challenging conditions similar to those encountered in circulation. This phenotype was largely associated with context-specific modulation of survival pathways, including β-catenin, pERK1/2, and BCL2, indicating a mechanoenvironment-mediated rewiring of survival pathways. Chemosensitivity assays further revealed that although PIEZO1 silencing sensitized the breast cancer cells to doxorubicin in static conditions, it enhanced drug resistance in anoikis-inducing conditions. Together, these findings uncover a dual, stage-specific role for PIEZO1 in breast cancer, in which optimal PIEZO1 activity sustains proliferation and invasion, whereas PIEZO1 loss enhances cell survival under mechanostress, thereby potentiating metastatic dissemination. These results highlight PIEZO1 as a mechanosensitive protein in breast cancer, and therapeutic modulation of PIEZO1 should consider the breast cancer subtype and mechanical microenvironment for optimal therapeutic outcomes.