TNFα-reliant FSP1 up-regulation promotes intervertebral disc degeneration via caspase 3-dependent apoptosis  

作　　者：Cheng Qiu Lin Cheng Derun Di Ziqian Xiang Congyu Wang Jinghang Li Yinuo Xiong Manyu Li Jingwei Liu Jian Zhou Tianyi Liu Xinyu Wang Dan Luo Xiaoxiong Wang Shangye Li Hui Wang Xia Wang Yunpeng Zhao Xinyu Liu Lianlei Wang 

机构地区：[1]Department of Orthopaedic Surgery,Qilu Hospital of Shandong University,Jinan,Shandong 250012,China [2]Cheeloo College of Medicine,Shandong University,Jinan,Shandong 250012,China [3]Department of Emergency Medicine,Qilu Hospital of Shandong University,Jinan,Shandong 250012,China [4]Department of Gastroenterology,Qilu Hospital of Shandong University,Jinan,Shandong 250012,China [5]Department of Pediatric Surgery,Qilu Hospital of Shandong University,Jinan,Shandong 250012,China [6]Department of Orthopedics,The Second Xiangya Hospital of Central South University,Changsha,Hunan 410011,China [7]Department of Medical Oncology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100021,China [8]Department of Molecular Orthopaedics,National Center for Orthopaedics,Beijing Research Institute of Traumatology and Orthopaedics,Beijing Jishuitan Hospital,Capital Medical University,Beijing 100035,China [9]Department of Oral and Maxillofacial Surgery,The Affiliated Hospital of Qingdao University,Qingdao,Shandong 266003,China

出　　处：《Genes & Diseases》2025年第1期327-340,共14页基因与疾病(英文)

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);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).

摘　　要：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.

关 键 词：Caspase 3 FSP1 iFSP1 Intervertebraldisc degeneration NF-ΚB TNFΑ 

分 类 号：R73[医药卫生—肿瘤]