Life sciences · 2026
ELF1 exacerbates intervertebral disc degeneration by promoting ACSL4-dependent ferro-aging of nucleus pulposus cells through the IFITM3-PTPRO axis.
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Lu Jia-Hao, Huang Shan-Shan, Xu Hao-Wei, Zhang Shu-Bao, Chang Sheng-Jie, Wu Fei-Yang, Liu Xiao-Wei, Wang Shan-Jin
Аннотация
AIMS: Intervertebral disc degeneration (IVDD) is a major cause of low back pain and is characterized by nucleus pulposus cell (NPC) senescence and extracellular matrix degradation. Ferro-aging, a chronic iron-dependent lipid peroxidation-associated senescence program, has recently been proposed as a potential mechanism linking metabolic dysregulation with tissue aging. However, whether ferro-aging contributes to IVDD and how it is regulated remain unclear. This study aimed to investigate the role of ferro-aging in IVDD and identify its upstream regulatory network.
MATERIALS AND METHODS: Single-cell RNA sequencing analysis, human nucleus pulposus tissue validation, puncture-induced and age-related IVDD animal models, and multiple NPC senescence models were used to investigate IFITM3-associated ferro-aging. Loss- and gain-of-function approaches, RNA sequencing, co-immunoprecipitation, dual-luciferase reporter assays, and chromatin immunoprecipitation assays were performed to investigate the regulatory network involving ELF1, IFITM3, PTPRO, and ACSL4.
KEY FINDINGS: IFITM3 showed increased expression in degenerated NPCs and was associated with ferroptosis-related pathways, inflammatory responses, and extracellular matrix remodeling. IFITM3 promoted NPC ferro-aging by enhancing iron accumulation, ACSL4 expression, lipid peroxidation, oxidative stress, and cellular senescence. Mechanistically, PTPRO was identified as an IFITM3-associated regulatory node that contributes to ACSL4 protein stabilization and lipid peroxidation, while ELF1 transcriptionally activates IFITM3. Genetic inhibition of Ifitm3, Ptpro, or Elf1 alleviated ferro-aging phenotypes and attenuated IVDD progression.
SIGNIFICANCE: This study identifies ferro-aging as a previously unrecognized mechanism contributing to IVDD and identifies a regulatory network involving ELF1, IFITM3, PTPRO, and ACSL4 as a potential therapeutic framework for delaying disc degeneration.
MATERIALS AND METHODS: Single-cell RNA sequencing analysis, human nucleus pulposus tissue validation, puncture-induced and age-related IVDD animal models, and multiple NPC senescence models were used to investigate IFITM3-associated ferro-aging. Loss- and gain-of-function approaches, RNA sequencing, co-immunoprecipitation, dual-luciferase reporter assays, and chromatin immunoprecipitation assays were performed to investigate the regulatory network involving ELF1, IFITM3, PTPRO, and ACSL4.
KEY FINDINGS: IFITM3 showed increased expression in degenerated NPCs and was associated with ferroptosis-related pathways, inflammatory responses, and extracellular matrix remodeling. IFITM3 promoted NPC ferro-aging by enhancing iron accumulation, ACSL4 expression, lipid peroxidation, oxidative stress, and cellular senescence. Mechanistically, PTPRO was identified as an IFITM3-associated regulatory node that contributes to ACSL4 protein stabilization and lipid peroxidation, while ELF1 transcriptionally activates IFITM3. Genetic inhibition of Ifitm3, Ptpro, or Elf1 alleviated ferro-aging phenotypes and attenuated IVDD progression.
SIGNIFICANCE: This study identifies ferro-aging as a previously unrecognized mechanism contributing to IVDD and identifies a regulatory network involving ELF1, IFITM3, PTPRO, and ACSL4 as a potential therapeutic framework for delaying disc degeneration.