Piezo1 channel exaggerates ferroptosis of nucleus pulposus cells by mediating mechanical stress-induced iron influx

To date,several molecules have been found to facilitate iron influx,while the types of iron influx channels remain to be elucidated.Here,Piezo1 channel was identified as a key iron transporter in response to mechanical stress.Piezo1-mediated iron overload disturbed iron metabolism and exaggerated ferroptosis in nucleus pulposus cells(NPCs).Importantly,Piezo1-induced iron influx was independent of the transferrin receptor(TFRC),a well-recognized iron gatekeeper.Furthermore,pharmacological inactivation of Piezo1 profoundly reduced iron accumulation,alleviated mitochondrial ROS,and suppressed ferroptotic alterations in stimulation of mechanical stress.Moreover,conditional knockout of Piezo1(Col2a1-CreERT Piezo1^(flox/flox))attenuated the mechanical injury-induced intervertebral disc degeneration(IVDD).Notably,the protective effect of Piezo1 deficiency in IVDD was dampened in Piezo1/Gpx4 conditional double knockout(cDKO)mice(Col2a1-CreERT Piezo1^(flox/flox)/Gpx4^(flox/flox)).These findings suggest that Piezo1 is a potential determinant of iron influx,indicating that the Piezo1-iron-ferroptosis axis might shed light on the treatment of mechanical stress-induced diseases.