Targeting the Mechanosensitive Channel Piezo2 Alleviates Intracerebral Hemorrhage-induced Brain Injury by Modulating ER Stress.

Secondary brain injury (SBI) following intracerebral hemorrhage (ICH) is heavily driven by the mechanical compression of the expanding hematoma, yet how neurons transduce this physical force into pathological intracellular signals remains poorly understood. This study investigates the role of the mechanosensitive ion channel Piezo2 in ICH-induced SBI and its underlying molecular mechanisms. Using a collagenase-induced ICH mouse model and single-cell RNA sequencing analysis, we identified a marked upregulation of Piezo2 in perihematomal neurons. To determine its functional significance, we employed both genetic knockdown (shRNA) and pharmacological modulation with D-GsMTx4 in vivo. Modulation of Piezo2 significantly alleviated acute neurological deficits, reduced brain edema, and improved long-term cognitive performance in ICH mice. Mechanistically, we observed that the neuroprotective effects of Piezo2 inhibition were associated with an attenuation of neuronal endoplasmic reticulum (ER) stress. Specifically, inhibition of Piezo2 preserved ER ultrastructure, which was accompanied by a robust downregulation of the PERK/ATF4/CHOP signaling cascade markers. Collectively, our findings suggest that Piezo2 contributes to neuronal damage following ICH and that its modulation impacts ER stress. Targeting Piezo2 represents a novel experimental concept to mitigate secondary neurodegeneration associated with hematoma-induced mechanical strain, though extensive preclinical optimization is required before considering its clinical viability.