International immunopharmacology · 2025
Deferoxamine improves intervertebral disc degeneration by activating HIF-1α/BNIP3-mediated mitophagy and inhibiting ferroptosis.
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Wang Heran, Zhou Zimo, Wu Tong, Fan Zheng, Jin Zhuoru, Cao Yuxiao, Huangfu Chenhao, Wang Yulin, Liu Xiaodong, Liu Da
Аннотация
BACKGROUND: Intervertebral disc degeneration (IVDD), a major cause of low back pain, is characterized by cartilage endplate (CEP) degeneration, extracellular matrix (ECM) degradation, and oxidative stress. Deferoxamine (DFO), an iron chelator, demonstrates efficacy in treating iron-overload disorders.
OBJECTIVE: This study aimed to systematically investigate the role and molecular mechanisms of DFO in IVDD and ferroptosis.
METHODS: We employed bioinformatics analysis, in vitro cell models, and an in vivo mouse IVDD model.
RESULTS: Bioinformatics identified 65 common targets for DFO and IVDD, implicating mitochondrial function regulation, oxidative stress response, and the HIF-1α signaling pathway. In vitro, 100 μM DFO restored tert-butyl hydroperoxide (TBHP)-induced suppression of superoxide dismutase (SOD) activity, enhanced COL2 and SOX9 expression, and suppressed MMP3, COL10, and RUNX2 expression, mitigating calcification. In vivo, 100 mg/kg/day for 12 weeks DFO alleviated IVDD pathology in the IVDD model. DFO promoted mitochondrial autophagy (mitophagy) via the HIF-1α/BNIP3 axis, reduced malondialdehyde (MDA) levels, and increased glutathione (GSH) and GPX4 expression. Mechanistic studies confirmed that DFO inhibits ferroptosis and CEP degeneration by activating HIF-1α/BNIP3-mediated mitophagy.
CONCLUSION: DFO ameliorates CEP degeneration in IVDD by targeting oxidative stress, ferroptosis, and mitochondrial dysfunction. Its protective effects are mediated through multi-targeted mechanisms, prominently involving the activation of HIF-1α/BNIP3-mediated mitophagy to suppress ferroptosis. These findings highlight DFO as a promising therapeutic strategy for IVDD and ferroptosis-related pathologies.
OBJECTIVE: This study aimed to systematically investigate the role and molecular mechanisms of DFO in IVDD and ferroptosis.
METHODS: We employed bioinformatics analysis, in vitro cell models, and an in vivo mouse IVDD model.
RESULTS: Bioinformatics identified 65 common targets for DFO and IVDD, implicating mitochondrial function regulation, oxidative stress response, and the HIF-1α signaling pathway. In vitro, 100 μM DFO restored tert-butyl hydroperoxide (TBHP)-induced suppression of superoxide dismutase (SOD) activity, enhanced COL2 and SOX9 expression, and suppressed MMP3, COL10, and RUNX2 expression, mitigating calcification. In vivo, 100 mg/kg/day for 12 weeks DFO alleviated IVDD pathology in the IVDD model. DFO promoted mitochondrial autophagy (mitophagy) via the HIF-1α/BNIP3 axis, reduced malondialdehyde (MDA) levels, and increased glutathione (GSH) and GPX4 expression. Mechanistic studies confirmed that DFO inhibits ferroptosis and CEP degeneration by activating HIF-1α/BNIP3-mediated mitophagy.
CONCLUSION: DFO ameliorates CEP degeneration in IVDD by targeting oxidative stress, ferroptosis, and mitochondrial dysfunction. Its protective effects are mediated through multi-targeted mechanisms, prominently involving the activation of HIF-1α/BNIP3-mediated mitophagy to suppress ferroptosis. These findings highlight DFO as a promising therapeutic strategy for IVDD and ferroptosis-related pathologies.