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HIF-1α Induced by Hypoxia Promotes Peripheral Nerve Injury Recovery Through Regulating Ferroptosis in DRG Neuron

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Abstract

Peripheral nerve injury (PNI) usually has a poor effect on functional recovery and severely declines the patient’s quality of life. Our prior findings indicated that hypoxia remarkably promoted nerve regeneration of rats with sciatic nerve transection. However, the underlying molecular mechanisms of hypoxia in functional recovery of PNI still remain elusive. In this research, we tried to explain the functional roles and mechanisms of hypoxia and the hypoxia-inducible factor-1α (HIF-1α) in PNI. Our results indicated that hypoxia promoted proliferation and migration of dorsal root ganglia (DRG) and increased the expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Mechanistically, hypoxia suppressed ferroptosis through activating HIF-1α in DRG neurons. Gain and loss of function studies were performed to evaluate the regulatory roles of HIF-1α in ferroptosis and neuron recovery. The results revealed that up-regulation of HIF-1α enhanced the expression of solute carrier family membrane 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) and increased the contents of cysteine and glutathione, while inhibiting the accumulation of reactive oxygen species (ROS). Our findings provided novel light on the mechanism of ferroptosis involved in PNI and manifest hypoxia as a potential therapeutic strategy for PNI recovery.

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Data Availability

The raw data during this study are available from the corresponding authors on reasonable request.

Abbreviations

PNI:

Peripheral nerve injury

HIF-1α:

Hypoxia-inducible factor-1α

DRG:

Dorsal root ganglia

BDNF:

Brain-derived neurotrophic factor

NGF:

Nerve growth factor

SLC7A11:

Solute carrier family membrane 11

GPX4:

Glutathione peroxidase 4

ROS:

Reactive oxygen species

GDNF:

Glial cell line-derived neurotrophic factor

PHD:

Prolyl hydroxylase domain

TBI:

Traumatic brain injury

Fer-1:

Ferrostatin-1

ACR:

Acrylamide

MMP:

Mitochondrial membrane potential

EDU:

Ethynyl deoxyuridine

TEM:

Transmission electron microscopy

References

  1. Zhang S, Huang M, Zhi J, Wu S, Wang Y, Pei F (2023) Research Hotspots and trends of peripheral nerve injuries based on web of science from 2017 to 2021: a bibliometric analysis. Front Neurol 13:872261

    Article  Google Scholar 

  2. Lavorato A, Aruta G, De Marco R, Zeppa P, Titolo P, Colonna MR, Galeano M, Costa AL et al (2023) Traumatic peripheral nerve injuries: a classification proposal. J Orthop Traumatol 24:20

    Article  PubMed  PubMed Central  Google Scholar 

  3. Liu Y, Zhang X, Xiao C, Liu B (2023) Engineered hydrogels for peripheral nerve repair. Mater Today Bio 20:100668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bradke F (2022) Mechanisms of axon growth and regeneration: moving between development and disease. J Neurosci 42:8393–8405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wang X, Li W, Zhang J, Li J, Zhang X, Wang M, Wei Z, Feng S (2023) Discovery of therapeutic targets for spinal cord injury based on molecular mechanisms of axon regeneration after conditioning lesion. J Transl Med 21:511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Guo Q, Li X, Li W, Wang R, Zhao A, Wang Z (2023) A pharmacodynamic evaluation of the protective effects of roxadustat against hypoxic injury at high altitude. Drug Des Devel Ther 17:75–85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Guo C, Zhang M, Su W, Xu M, Zhao S (2022) miR-199a-5p relieves obstructive sleep apnea syndrome-related hypertension by targeting HIF-1α. J Immunol Res 2022:7236647

    Article  PubMed  PubMed Central  Google Scholar 

  8. Tang YY, Wang DC, Wang YQ, Huang AF, Xu WD (2023) Emerging role of hypoxia-inducible factor-1α in inflammatory autoimmune diseases: a comprehensive review. Front Immunol 13:1073971

    Article  PubMed  PubMed Central  Google Scholar 

  9. Wang M, Wang D, Lang Y, Shao A, Zhang R, Tang J, Lai D, Xiao C (2023) L3MBTL3 is induced by HIF-1α and fine tunes the HIF-1α degradation under hypoxia in vitro. Heliyon 9:e13222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. DeFrates KG, Franco D, Heber-Katz E, Messersmith PB (2021) Unlocking mammalian regeneration through hypoxia inducible factor one alpha signaling. Biomaterials 269:120646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. An S, Zhou M, Li Z, Feng M, Cao G, Lu S, Liu L (2018) Administration of CoCl2 improves functional recovery in a rat model of sciatic nerve transection injury. Int J Med Sci 15:1423–1432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yeoh S, Warner WS, Merchant SS, Hsu EW, Agoston DV, Mahan MA (2022) Incorporating blood flow in nerve injury and regeneration assessment. Front Surg 9:862478

    Article  PubMed  PubMed Central  Google Scholar 

  13. Pu F, Chen F, Zhang Z, Shi D, Zhong B, Lv X, Tucker AB, Fan J et al (2022) Ferroptosis as a novel form of regulated cell death: implications in the pathogenesis, oncometabolism and treatment of human cancer. Genes Dis 9:347–357

    Article  CAS  PubMed  Google Scholar 

  14. Zhang C, Liu X, Jin S, Chen Y, Guo R (2022) Ferroptosis in cancer therapy: a novel approach to reversing drug resistance. Mol Cancer 21:47

    Article  PubMed  PubMed Central  Google Scholar 

  15. Xia Y, Wang H, Xie Z, Liu ZH, Wang HL (2023) Inhibition of ferroptosis underlies EGCG mediated protection against Parkinson’s disease in a Drosophila model. Free Radic Biol Med 211:63–76

    Article  PubMed  Google Scholar 

  16. Chavoshinezhad S, Beirami E, Izadpanah E, Feligioni M, Hassanzadeh K (2023) Molecular mechanism and potential therapeutic targets of necroptosis and ferroptosis in Alzheimer’s disease. Biomed Pharmacother 168:115656

    Article  CAS  PubMed  Google Scholar 

  17. Fang J, Yuan Q, Du Z, Zhang Q, Yang L, Wang M, Yang W, Yuan C et al (2023) Overexpression of GPX4 attenuates cognitive dysfunction through inhibiting hippocampus ferroptosis and neuroinflammation after traumatic brain injury. Free Radic Biol Med 204:68–81

    Article  CAS  PubMed  Google Scholar 

  18. Chen J, Zhu T, Yu D, Yan B, Zhang Y, Jin J, Yang Z, Zhang B et al (2023) Moderate intensity of treadmill exercise rescues TBI-induced ferroptosis, neurodegeneration, and cognitive impairments via suppressing STING pathway. Mol Neurobiol 60:4872–4896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Xie BS, Wang YQ, Lin Y, Mao Q, Feng JF, Gao GY, Jiang JY (2019) Inhibition of ferroptosis attenuates tissue damage and improves long-term outcomes after traumatic brain injury in mice. CNS Neurosci Ther 25:465–475

    Article  CAS  PubMed  Google Scholar 

  20. Shen Z, Beckel J, de Groat WC, Tai C (2023) Effect of high-frequency membrane potential alternation between depolarization and hyperpolarization on dorsal root ganglion neurons of rats. Physiol Rep 11:e15582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hidaka K, Maruta T, Koshida T, Kurogi M, Kage Y, Kouroki S, Shirasaka T, Takeya R et al (2022) Extracellular signal-regulated kinase phosphorylation enhancement and NaV1.7 sodium channel upregulation in rat dorsal root ganglia neurons contribute to resiniferatoxin-induced neuropathic pain: the efficacy and mechanism of pulsed radiofrequency therapy. Mol Pain 18:17448069221089784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang S, Zhang Y, Lou J, Yong H, Shan S, Liu Z, Song M, Zhang C et al (2023) The therapeutic potential of berberine chloride against SARM1-dependent axon degeneration in acrylamide-induced neuropathy. Phytother Res 37:77–88

    Article  CAS  PubMed  Google Scholar 

  23. Chen X, Xiao J, Fu H, Zhang Y, Li Y, Yang H, Gao W, Li B (2022) Acrylamide-induced damage to postsynaptic plasticity is CYP2E1 dependent in an SH-SY5Y co-culture system. Toxicol In Vitro 84:105455

    Article  CAS  PubMed  Google Scholar 

  24. Gao Y, Nie Z, Cao H, Huang D, Chen M, Xiang Y, Yu X, Zhang S (2022) Scabertopin derived from Elephantopus scaber L. mediates necroptosis by inducing reactive oxygen species production in bladder cancer in vitro. Cancers (Basel) 14:5976

    Article  CAS  PubMed  Google Scholar 

  25. Yang L, Cao LM, Zhang XJ, Chu B (2022) Targeting ferroptosis as a vulnerability in pulmonary diseases. Cell Death Dis 13:649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Xue X, Ma L, Zhang X, Xu X, Guo S, Wang Y, Qiu S, Cui J et al (2022) Tumour cells are sensitised to ferroptosis via RB1CC1-mediated transcriptional reprogramming. Clin Transl Med 12:e747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hassan K, Matio Kemkuignou B, Kirchenwitz M, Wittstein K, Rascher-Albaghdadi M, Chepkirui C, Matasyoh JC, Decock C et al (2022) Neurotrophic and immunomodulatory lanostane triterpenoids from wood-inhabiting basidiomycota. Int J Mol Sci 23:13593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang Y, Xiong ZL, Ma XL, Zhou C, Huo MH, Jiang XW, Yu WH (2022) Acetyl-11-keto-beta-boswellic acid promotes sciatic nerve repair after injury: molecular mechanism. Neural Regen Res 17:2778–2784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. He W, Shu W, Xue L, Wang Y, Chai Y, Wu H, Wang Z (2022) Synergistic effect of erastin combined with nutlin-3 on vestibular schwannoma cells as p53 modulates erastin-induced ferroptosis response. J Oncol 2022:7507857

    Article  PubMed  PubMed Central  Google Scholar 

  30. Xiao Z, Shen D, Lan T, Wei C, Wu W, Sun Q, Luo Z, Chen W et al (2022) Reduction of lactoferrin aggravates neuronal ferroptosis after intracerebral hemorrhagic stroke in hyperglycemic mice. Redox Biol 50:102256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Tang B, Yan R, Zhu J, Cheng S, Kong C, Chen W, Fang S, Wang Y et al (2022) Integrative analysis of the molecular mechanisms, immunological features and immunotherapy response of ferroptosis regulators across 33 cancer types. Int J Biol Sci 18:180–198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Byun JK, Lee S, Kang GW, Lee YR, Park SY, Song IS, Yun JW, Lee J et al (2022) Macropinocytosis is an alternative pathway of cysteine acquisition and mitigates sorafenib-induced ferroptosis in hepatocellular carcinoma. J Exp Clin Cancer Res 41:98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cao Z, Qin H, Huang Y, Zhao Y, Chen Z, Hu J, Gao Q (2022) Crosstalk of pyroptosis, ferroptosis, and mitochondrial aldehyde dehydrogenase 2-related mechanisms in sepsis-induced lung injury in a mouse model. Bioengineered 13:4810–4820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu T, Wang Y, Lu L, Liu Y (2022) SPIONs mediated magnetic actuation promotes nerve regeneration by inducing and maintaining repair-supportive phenotypes in Schwann cells. J Nanobiotechnology 20:159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sala-Jarque J, Mesquida-Veny F, Badiola-Mateos M, Samitier J, Hervera A, Del Río JA (2020) Neuromuscular activity induces paracrine signaling and triggers axonal regrowth after injury in microfluidic lab-on-chip devices. Cells 9:302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Stockwell BR, Jiang X (2020) The chemistry and biology of ferroptosis. Cell Chem Biol 27:365–375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chen X, Yu C, Kang R, Kroemer G, Tang D (2021) Cellular degradation systems in ferroptosis. Cell Death Differ 28:1135–1148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Noh B, Blasco-Conesa MP, Rahman SM, Monga S, Ritzel R, Guzman G, Lai YJ, Ganesh BP et al (2023) Iron overload induces cerebral endothelial senescence in aged mice and in primary culture in a sex-dependent manner. Aging Cell 22:e13977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tu LF, Zhang TZ, Zhou YF, Zhou QQ, Gong HB, Liang L, Hai LN, You NX et al (2023) GPX4 deficiency-dependent phospholipid peroxidation drives motor deficits of ALS. J Adv Res 43:205–218

    Article  CAS  PubMed  Google Scholar 

  40. Liu X, Chen C, Han D, Zhou W, Cui Y, Tang X, Xiao C, Wang Y et al (2022) SLC7A11/GPX4 inactivation-mediated ferroptosis contributes to the pathogenesis of triptolide-induced cardiotoxicity. Oxid Med Cell Longev 2022:3192607

    PubMed  PubMed Central  Google Scholar 

  41. Zhao L, Zhou X, Xie F, Zhang L, Yan H, Huang J, Zhang C, Zhou F et al (2022) Ferroptosis in cancer and cancer immunotherapy. Cancer Commun 42:88–116

    Article  Google Scholar 

  42. Wang Y, Wu X, Ren Z, Li Y, Zou W, Chen J, Wang H (2023) Overcoming cancer chemotherapy resistance by the induction of ferroptosis. Drug Resist Updat 66:100916

    Article  CAS  PubMed  Google Scholar 

  43. Guo Y, Du J, Xiao C, Xiang P, Deng Y, Hei Z, Li X (2021) Inhibition of ferroptosis-like cell death attenuates neuropathic pain reactions induced by peripheral nerve injury in rats. Eur J Pain 25:1227–1240

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to acknowledge our lab colleagues for the support in the work of this study.

Funding

The research was supported by the Capital Health Research and Development of Special (2020–4-2018) and Beijing Natural Science Foundation (Grant No. 7232073).

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Authors and Affiliations

  1. Department of Orthopedics, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China

    Shuai An, Jiang Huang, Zheng Li, Mingli Feng & Guanglei Cao

  2. Cerebrovascular and Neuroscience Research Institute, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, Beijing, China

    Jingfei Shi

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Contributions

S.A. conceived the experiment, S.A., J.S. J.H., and Z.L. conducted the experiment; M.F., G.C, and S.A. analyzed the results. S.A and J.S. drafted the manuscript. All authors reviewed the manuscript.

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Correspondence to Mingli Feng or Guanglei Cao.

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Shuai An and Jingfei Shi contributed equally to the work.

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An, S., Shi, J., Huang, J. et al. HIF-1α Induced by Hypoxia Promotes Peripheral Nerve Injury Recovery Through Regulating Ferroptosis in DRG Neuron. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-03964-5

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