Inhibition of Piezo1 ameliorates septic cardiomyopathy by blocking calcium-dependent PANoptosis

Sepsis-induced cardiomyopathy (SIC) represents a severe and often fatal complication of sepsis, characterized by significant mortality. Despite extensive research, the underlying mechanisms remain incompletely understood. Recent studies have highlighted PANoptosis, an emerging form of programmed cell death, as a critical factor in inflammatory diseases. Piezo1, a mechanosensitive ion channel, has been implicated in various pathological conditions; however, its role in SIC and its involvement in PANoptosis require further investigation. In this study, the role of Piezo1 in SIC and calcium-dependent PANoptosis were investigated. SIC was induced in mice via cecal ligation and puncture (CLP), and the effects of Piezo1 inhibition on cardiac function, histological changes, mitochondrial function, and PANoptosis were assessed. Our results show that sepsis upregulates Piezo1 expression in cardiomyocytes through TLR4-NF-kappa B signaling. Pharmacological blockade of Piezo1 with its inhibitor GsMTx4 attenuated CLP-induced cardiac injury, histological damage, and mitochondrial dysfunction. Importantly, Piezo1 inhibition also significantly suppressed PANoptosis in septic hearts. In vitro experiments with Piezo1 siRNA, GsMTx4 and the calcium chelator BAPTA confirmed that inhibition of Piezo1 attenuates LPSinduced PANoptosis by limiting calcium release in cardiomyocytes after LPS treatment, linking Piezo1 to the regulation of these key events. Collectively, these findings reveal Piezo1 as a novel mechanosensor for sepsis and reveal a previously unrecognized role of Piezo1 in the activation of calcium-mediated PANoptosis in SIC. Given the ability of Piezo1 inhibition to mitigate key pathological features of SIC, targeting Piezo1 represents a promising therapeutic strategy for improving the outcomes of sepsis-related cardiac dysfunction.