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Role and mechanism of AOPPs-induced NOX4-mediated ferroptosis in intervertebral disc degeneration

Kewu Tu1, Kun Zhao2, Dongteng Liao2

  • 1Department of Spinal Surgery, Shaoguan First People's Hospital, Shaoguan, China.

Scientific Reports
|July 2, 2026
PubMed

Insights

Advanced oxidation protein products (AOPPs) trigger ferroptosis, a cell death pathway, in intervertebral disc degeneration (IVDD) by activating NADPH oxidase 4 (NOX4). Targeting NOX4 may offer new treatments for low back pain caused by IVDD.

Area of Science:

  • Biomedical Science
  • Cell Biology
  • Orthopedics

Background:

  • Intervertebral disc degeneration (IVDD) is a primary cause of low back pain, involving matrix degradation and loss of disc height.
  • Ferroptosis, a form of regulated cell death driven by lipid peroxidation, is increasingly recognized in IVDD, but its upstream triggers in disc cells are not fully understood.
  • Advanced oxidation protein products (AOPPs) are markers of oxidative stress found in degenerated discs and are known to activate NADPH oxidase 4 (NOX4).

Purpose of the Study:

  • To investigate the role of AOPPs in inducing ferroptosis in intervertebral disc cells.
  • To determine if NADPH oxidase 4 (NOX4) mediates AOPP-induced ferroptosis and contributes to IVDD.
  • To explore the potential of targeting NOX4 as a therapeutic strategy for IVDD.

Main Methods:

  • A rat puncture-induced IVDD model was used, with intradiscal administration of AOPPs.
  • In vitro studies involved treating nucleus pulposus and annulus fibrosus cells with AOPPs and ferroptosis inducers.
  • NOX4 inhibition was achieved using pharmacological inhibitors and genetic knockdown (siRNA).
  • Ferroptosis was assessed by measuring lipid peroxidation products (MDA), iron levels, glutathione (GSH) levels, mitochondrial morphology, and ferroptosis-related protein expression (GPX4, FTH, TXNIP).

Main Results:

  • Intradiscal AOPPs administration worsened IVDD in rats, characterized by reduced disc height, matrix degradation, and altered expression of NOX4, TXNIP, FTH, and GPX4.
  • In vitro, AOPPs induced ferroptotic changes in disc cells, including increased MDA, iron accumulation, GSH depletion, and mitochondrial dysfunction, which were reversed by the ferroptosis inhibitor Ferrostatin-1.
  • Inhibition or knockdown of NOX4 significantly attenuated AOPP-induced ferroptosis in vitro and protected against IVDD progression in vivo.

Conclusions:

  • AOPPs induce ferroptosis in intervertebral disc cells through the activation of NOX4.
  • NOX4 acts as a key regulator in the ferroptosis pathway contributing to the pathogenesis of IVDD.
  • Targeting NOX4 to inhibit ferroptosis presents a promising therapeutic avenue for managing IVDD and associated low back pain.
Keywords:
Advanced oxidation protein productsFerroptosisIntervertebral disc degenerationNADPH oxidase 4

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