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

Ziqian Xiang1,2, Pengfei Zhang1, Chunwang Jia1, Rongkun Xu1, Dingren Cao3, Zhaoning Xu4, Tingting Lu5, Jingwei Liu6, Xiaoxiong Wang1,2, Cheng Qiu1, Wenyang Fu1, Weiwei Li7, Lei Cheng1, Qiang Yang8, Shiqing Feng1, 9, Lianlei Wang1, Yunpeng Zhao1, Xinyu Liu1

Bone Research ›› 2024, Vol. 12 ›› Issue (0) : 20. DOI: 10.1038/s41413-024-00317-9

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

  • Ziqian Xiang1,2, Pengfei Zhang1, Chunwang Jia1, Rongkun Xu1, Dingren Cao3, Zhaoning Xu4, Tingting Lu5, Jingwei Liu6, Xiaoxiong Wang1,2, Cheng Qiu1, Wenyang Fu1, Weiwei Li7, Lei Cheng1, Qiang Yang8, Shiqing Feng1, 9, Lianlei Wang1, Yunpeng Zhao1, Xinyu Liu1
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Abstract

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 Piezo1flox/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 Piezo1flox/flox/Gpx4flox/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.

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Ziqian Xiang, Pengfei Zhang, Chunwang Jia, Rongkun Xu, Dingren Cao, Zhaoning Xu, Tingting Lu, Jingwei Liu, Xiaoxiong Wang, Cheng Qiu, Wenyang Fu, Weiwei Li, Lei Cheng, Qiang Yang, Shiqing Feng, Lianlei Wang, Yunpeng Zhao, Xinyu Liu. Piezo1 channel exaggerates ferroptosis of nucleus pulposus cells by mediating mechanical stress-induced iron influx. Bone Research, 2024, 12(0): 20 https://doi.org/10.1038/s41413-024-00317-9

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Funding
Lianlei Wang (wanglianlei123@163.com) or Yunpeng Zhao (yunpengzhaoqlyy@gmail.com) or Xinyu Liu (newyuliu@163.com)

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