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 mechanica...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.展开更多
Intervertebral disc degeneration(IDD)is a common chronic inflammatory degenerative disease that causes lower back pain.However,the underlying mechanisms of IDD remain unclear.Ferroptosis suppressor protein 1(FSP1)is a...Intervertebral disc degeneration(IDD)is a common chronic inflammatory degenerative disease that causes lower back pain.However,the underlying mechanisms of IDD remain unclear.Ferroptosis suppressor protein 1(FSP1)is a newly identified suppressor for ferroptosis.This study aims to investigate the role of FSP1 in IDD.Nucleus pulposus(NP)tissues in humans were collected and NP cells from rats were isolated to detect FSP1 expression pattern.The relationship between FSP1-mediated ferroptosis and apoptosis was identified using FSP1 inhibitor iFSP1.RNA sequencing was utilized to seek downstream molecules and related signaling pathways.Moreover,both exogenous recombinant FSP1 protein and endogenous small interfering RNA were implemented in this study to clarify the role of FSP1 in tumor necrosis factor-alpha(TNFα)-mediated NP cell apoptosis.Ultimately,the underlying mechanisms of FSP1-related signaling pathway in IDD were uncovered both in vitro and in vivo.As a result,FSP1 was up-regulated in human degenerative NP tissues and after TNFαstimulation.FSP1 inhibition by iFSP1 fails to trigger ferroptosis in NP cells while inhibiting TNFα-mediated apoptosis.Further experiments demonstrated that FSP1 was closely related to TNFα-reliant caspase 3 activation and mitochondrial damage.However,the exogenous addition of recombinant protein FSP1 does not induce cell death or intensify the efficacy of TNFα.Mechanically,FSP1 is involved in TNFα-mediated NF-κB signaling activation to accelerate the development of IDD.This study demonstrated that FSP1 promotes IDD through TNFα-reliant NF-κB signaling activation and caspase 3-dependent apoptosis.These findings suggested a novel therapeutic target for the treatment of IDD.展开更多
基金supported in part by the National Nature Science Foundation(81874022 and 82172483 to Xinyu Liu,82102522 to Lianlei Wang,82072478 to Yunpeng Zhao,82072435 to Qiang Yang,82073437 to Weiwei Li,81930070 to Shiqing Feng,82272548 to Lei Cheng)Key R&D Project of Shandong Province(2022CXGC010503 to Xinyu Liu)+1 种基金Shandong Natural Science Foundation(ZR202102210113 to Lianlei Wang,ZR2020YQ54 to Yunpeng Zhao)Shandong Province Taishan Scholar Project(tsqn202211317 to Lianlei Wang).The authors thank the Translational Medicine Core Facility of Shandong University for the consultation and instrument availability that supported this work.
文摘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.
基金supported in part by the National Natural Science Foundation of China(No.81874022 and 82172483 to Xinyu Liu,No.82102522 to Lianlei Wang)Key R&D Project of Shandong Province(China)(No.2022CXGC010503 to Xinyu Liu)+2 种基金Shandong Natural Science Foundation(No.ZR202102210113 to Lianlei Wang)Shandong Province Taishan Scholar Project(No.tsqn 202211317 to Lianlei Wang)National High Level Hospital Clinical Research Funding(No.2022-PUMCH-D-004).
文摘Intervertebral disc degeneration(IDD)is a common chronic inflammatory degenerative disease that causes lower back pain.However,the underlying mechanisms of IDD remain unclear.Ferroptosis suppressor protein 1(FSP1)is a newly identified suppressor for ferroptosis.This study aims to investigate the role of FSP1 in IDD.Nucleus pulposus(NP)tissues in humans were collected and NP cells from rats were isolated to detect FSP1 expression pattern.The relationship between FSP1-mediated ferroptosis and apoptosis was identified using FSP1 inhibitor iFSP1.RNA sequencing was utilized to seek downstream molecules and related signaling pathways.Moreover,both exogenous recombinant FSP1 protein and endogenous small interfering RNA were implemented in this study to clarify the role of FSP1 in tumor necrosis factor-alpha(TNFα)-mediated NP cell apoptosis.Ultimately,the underlying mechanisms of FSP1-related signaling pathway in IDD were uncovered both in vitro and in vivo.As a result,FSP1 was up-regulated in human degenerative NP tissues and after TNFαstimulation.FSP1 inhibition by iFSP1 fails to trigger ferroptosis in NP cells while inhibiting TNFα-mediated apoptosis.Further experiments demonstrated that FSP1 was closely related to TNFα-reliant caspase 3 activation and mitochondrial damage.However,the exogenous addition of recombinant protein FSP1 does not induce cell death or intensify the efficacy of TNFα.Mechanically,FSP1 is involved in TNFα-mediated NF-κB signaling activation to accelerate the development of IDD.This study demonstrated that FSP1 promotes IDD through TNFα-reliant NF-κB signaling activation and caspase 3-dependent apoptosis.These findings suggested a novel therapeutic target for the treatment of IDD.
