Piezo1 in the central nervous system: decoding the mechanical signature of neuroinflammation

Neuroinflammation has historically been viewed through a biochemical lens, governed by cytokines and danger signals. While this paradigm has provided foundational insights, integrating the physical dimension of tissue stiffening, hemodynamic shear stress, and compressive forces offers a more complete understanding of the pathological microenvironment of the central nervous system (CNS). In this Review, we examine Piezo1 as an important mechanosensitive channel that can translate such physical cues into neuroinflammatory responses. We synthesize emerging evidence showing that Piezo1-mediated calcium signaling can regulate activation, migration, and metabolic reprogramming in resident CNS cells and infiltrating immune populations. Importantly, the strength of evidence is not uniform across all cell types: genetic studies provide the strongest support in microglia, oligodendrocyte-lineage cells, and endothelial cells, whereas roles in astrocytes, dendritic cells, and T cells remain more context-dependent and emerging.Furthermore, we outline the distinct mechanical signatures across major CNS pathologies and discuss how Piezo1 may shape context-dependent outcomes-from plaque-associated microglial responses in Alzheimer's disease to mechanically restricted remyelination in multiple sclerosis, acute vascular or parenchymal injury in stroke and trauma, and emerging links to seizure-associated swelling and hyperexcitability in epilepsy. Finally, we propose an integrated "Mechanical Alterations-Piezo1-Immune Regulation" framework and discuss how mechano-therapeutic strategies might be used to modulate, rather than uniformly enhance or suppress, neuroinflammatory responses.