Sympathetic Overactivation Drives Neurogenic Alveolar Epithelial Pyroptosis via the PIEZO2 ‐ ER Stress Pathway in Acute Lung Injury Following Intracerebral Hemorrhage

AIMS: Intracerebral hemorrhage (ICH) frequently triggers acute lung injury (ALI) via sympathetic overactivation. We aimed to investigate the neuroinflammatory mechanisms driving this brain-lung crosstalk and evaluate targeted neuromodulatory interventions via the mechanosensor PIEZO2. METHODS: We utilized an ICH mouse model and norepinephrine (NE)-stimulated MLE12 cells. Pathological mechanisms were explored using transcriptomics, calcium imaging, and Vps35 knockdown. Therapeutic efficacies were assessed via central sympathetic blockade (stellate ganglion block, SGB) and peripheral PIEZO2 inhibition (D-GsMTx4). RESULTS: NE release exacerbated neurogenic ALI post-ICH. Mechanistically, NE upregulated VPS35, which simultaneously promoted PIEZO2 membrane trafficking and impaired ATP2A2-dependent endoplasmic reticulum (ER) calcium clearance. This induced massive intracellular calcium influx, triggering widespread ER stress and NLRP3/GSDMD-mediated pyroptosis in alveolar epithelial cells. Vps35 knockdown attenuated these effects in vitro. Crucially, targeted interventions with SGB or D-GsMTx4 successfully blocked this lethal central-peripheral cascade, alleviating pulmonary pyroptosis and improving in vivo outcomes. CONCLUSION: Sympathetic overactivation drives neurogenic ALI post-ICH via the VPS35/PIEZO2-ER stress-pyroptosis axis. Dual-node neuromodulation (SGB or PIEZO2 inhibition) offers a promising therapeutic strategy for secondary multiorgan complications following acute brain injury.