Roles and regulatory mechanisms of autophagy in the pathology of spinal cord injury

Zhiwan Chen; Jiajun Deng; Ruijin Huang; Zhisheng Ji

doi:10.1093/burnst/tkag058

Burns & Trauma ›› 2026, Vol. 14 ›› Issue (1) :tkag058 DOI: 10.1093/burnst/tkag058

Review

research-article

Roles and regulatory mechanisms of autophagy in the pathology of spinal cord injury

Zhiwan Chen ¹^,^‡
, Jiajun Deng ¹^,^‡
, Ruijin Huang ²^,^*
, Zhisheng Ji ¹^,^*

Author information +

History +

PDF (1950KB)

Abstract

Spinal cord injury (SCI) remains a major clinical challenge due to its limited therapeutic options and the resulting severe functional impairments. Autophagy is an essential intracellular degradation process that plays a critical role in maintaining cellular homeostasis by degrading and recycling abnormal proteins and toxic substances. Recent studies have shown that autophagy significantly regulates several key pathological processes in the acute phase of SCI, including oxidative stress and neuroinflammation, and may also influence axonal regeneration during subsequent repair stages. Pharmacological modulation of autophagic flux has shown therapeutic promise and may exert neuroprotective effects. However, the precise relationship between autophagy activation or inhibition and functional recovery remains controversial and has not been fully elucidated. This review systematically summarizes recent advances in understanding the role and regulatory mechanisms of autophagy in the pathological processes of SCI, with particular emphasis on current controversies and unresolved issues. It also outlines potential pharmacological strategies targeting autophagy and proposes future research directions to support the clinical translation of these therapeutic approaches.

Keywords

spinal cord injury / autophagy / inflammation / oxidative stress / axonal regeneration / autophagic flux / autophagy signaling pathways / neuroprotection / autophagy modulating drugs

Cite this article

Download citation ▾

Zhiwan Chen, Jiajun Deng, Ruijin Huang, Zhisheng Ji. Roles and regulatory mechanisms of autophagy in the pathology of spinal cord injury. Burns & Trauma, 2026, 14 (1) : tkag058 DOI:10.1093/burnst/tkag058

登录浏览全文

4963

注册一个新账户忘记密码

References

Publishing order | Descend order by publishing year | Descend order by cited within

[1]	Silva NA, Sousa N, Reis RL, Salgado AJ. From basics to clinical: a comprehensive review on spinal cord injury. Prog Neurobiol 2014; 114:25-57. https://doi.org/10.1016/j.pneurobio.2013.11.002.

[2]	Feng Z, Min L, Chen H, Deng W, Tan M, Liu H, et al. Iron overload in the motor cortex induces neuronal ferroptosis following spinal cord injury. Redox Biol 2021; 43:101984. https://doi.org/10.1016/j.redox.2021.101984.

[3]	Anjum A, Yazid MD, Fauzi Daud M, Idris J, Ng AMH, Selvi Naicker A, et al. Spinal cord injury: pathophysiology, multimolecular interactions, and underlying recovery mechanisms. Int J Mol Sci 2020; 21:7533. https://doi.org/10.3390/ijms21207533.

[4]	Ding Y, Chen Q. mTOR pathway: a potential therapeutic target for spinal cord injury. Biomed Pharmacother 2022; 145:112430. https://doi.org/10.1016/j.biopha.2021.112430.

[5]	Tran AP, Warren PM, Silver J. The biology of regeneration failure and success after spinal cord injury. Physiol Rev 2018; 98:881-917. https://doi.org/10.1152/physrev.00017.2017.

[6]	Alizadeh A, Dyck SM, Karimi-Abdolrezaee S. Traumatic spinal cord injury: an overview of pathophysiology, models and acute injury mechanisms. Front Neurol 2019; 10:282. https://doi.org/10.3389/fneur.2019.00282.

[7]	Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW, et al. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev 2010; 90:1383-435. https://doi.org/10.1152/physrev.00030.2009.

[8]	Mizushima N, Levine B. Autophagy in human diseases. N Engl J Med 2020; 383:1564-76. https://doi.org/10.1056/NEJMra2022774.

[9]	Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 2007; 8:741-52. https://doi.org/10.1038/nrm2239.

[10]	Guo F, Liu X, Cai H, Le W. Autophagy in neurodegenerative diseases: pathogenesis and therapy. Brain Pathol 2018; 28:3-13. https://doi.org/10.1111/bpa.12545.

[11]	Levy JMM, Towers CG, Thorburn A. Targeting autophagy in cancer. Nat Rev Cancer 2017; 17:528-42. https://doi.org/10.1038/nrc.2017.53.

[12]	Wong SQ, Kumar AV, Mills J, Lapierre LR. Autophagy in aging and longevity. Hum Genet 2020; 139:277-90. https://doi.org/10.1007/s00439-019-02031-7.

[13]	He Z, Du J, Zhang Y, Xu Y, Huang Q, Zhou Q, et al. Kruppel-like factor 2 contributes to blood-spinal cord barrier integrity and functional recovery from spinal cord injury by augmenting autophagic flux. Theranostics 2023; 13:849-66. https://doi.org/10.7150/thno.74324.

[14]	Li Y, Lei Z, Ritzel RM, He J, Li H, Choi HMC, et al. Impairment of autophagy after spinal cord injury potentiates neuroinflammation and motor function deficit in mice. Theranostics 2022; 12:5364-88. https://doi.org/10.7150/thno.72713.

[15]	Alizadeh J, Kochan MM, Stewart VD, Drewnik DA, Hannila SS, Ghavami S. Inhibition of autophagy flux promotes secretion of chondroitin sulfate proteoglycans in primary rat astrocytes. Mol Neurobiol 2021; 58:6077-91. https://doi.org/10.1007/s12035-021-02533-4.

[16]	Zhang L, Xiao Z, Su Z, Wang X, Tian H, Su M. Repetitive transcranial magnetic stimulation promotes motor function recovery in mice after spinal cord injury via regulation of the Cx43-autophagy loop. J Orthop Surg Res 2024; 19:387. https://doi.org/10.1186/s13018-024-04879-6.

[17]	Saraswat Ohri S, Bankston AN, Mullins SA, Liu Y, Andres KR, Beare JE, et al. Blocking autophagy in oligodendrocytes limits functional recovery after spinal cord injury. J Neurosci 2018; 38:5900-12. https://doi.org/10.1523/jneurosci.0679-17.2018.

[18]	Kaushik S, Cuervo AM. The coming of age of chaperone-mediated autophagy. Nat Rev Mol Cell Biol 2018; 19:365-81. https://doi.org/10.1038/s41580-018-0001-6.

[19]	Zientara-Rytter K, Subramani S. Autophagic degradation of peroxisomes in mammals. Biochem Soc Trans 2016; 44:431-40. https://doi.org/10.1042/bst20150268.

[20]	Vargas JNS, Hamasaki M, Kawabata T, Youle RJ, Yoshimori T. The mechanisms and roles of selective autophagy in mammals. Nat Rev Mol Cell Biol 2023; 24:167-85. https://doi.org/10.1038/s41580-022-00542-2.

[21]	Wang S, Long H, Hou L, Feng B, Ma Z, Wu Y, et al. The mitophagy pathway and its implications in human diseases. Signal Transduct Target Ther 2023; 8:304. https://doi.org/10.1038/s41392-023-01503-7.

[22]	Chen D, Zhou L, Chen G, Lin T, Lin J, Zhao X, et al. FUNDC1-induced mitophagy protects spinal cord neurons against ischemic injury. Cell Death Discov 2024; 10:4. https://doi.org/10.1038/s41420-023-01780-9.

[23]	Handa K, Kanno H, Matsuda M, Sugaya T, Murakami T, Prudnikova M, et al. Chaperone-mediated autophagy after spinal cord injury. J Neurotrauma 2020; 37:1687-95. https://doi.org/10.1089/neu.2019.6820.

[24]	Fu D, Li Z, Feng H, Fan F, Zhang W, He L. Chaperone mediated autophagy modulates microglia polarization and inflammation via LAMP2A in ischemia induced spinal cord injury. Toxicol Res (Camb) 2025; 14:tfaf061. https://doi.org/10.1093/toxres/tfaf061.

[25]	Parzych KR, Klionsky DJ. An overview of autophagy: morphology, mechanism, and regulation. Antioxid Redox Signal 2014; 20:460-73. https://doi.org/10.1089/ars.2013.5371.

[26]	Zhou K, Sansur CA, Xu H, Jia X. The temporal pattern, flux, and function of autophagy in spinal cord injury. Int J Mol Sci 2017; 18:466. https://doi.org/10.3390/ijms18020466.

[27]	Noda NN, Inagaki F. Mechanisms of autophagy. Annu Rev Biophys 2015; 44:101-22. https://doi.org/10.1146/annurev-biophys-060414-034248.

[28]	Zachari M, Ganley IG. The mammalian ULK1 complex and autophagy initiation. Essays Biochem 2017; 61:585-96. https://doi.org/10.1042/ebc20170021.

[29]	Galluzzi L, Bravo-San Pedro JM, Blomgren K, Kroemer G. Autophagy in acute brain injury. Nat Rev Neurosci 2016; 17:467-84. https://doi.org/10.1038/nrn.2016.51.

[30]	Kaur J, Debnath J. Autophagy at the crossroads of catabolism and anabolism. Nat Rev Mol Cell Biol 2015; 16:461-72. https://doi.org/10.1038/nrm4024.

[31]	Shao ZQ, Dou SS, Zhu JG, Wang HQ, Wang CM, Cheng BH, et al. Apelin-13 inhibits apoptosis and excessive autophagy in cerebral ischemia/reperfusion injury. Neural Regen Res 2021; 16:1044-51. https://doi.org/10.4103/1673-5374.300725.

[32]	Lumkwana D, du Toit A, Kinnear C, Loos B. Autophagic flux control in neurodegeneration: progress and precision targeting-where do we stand? Prog Neurobiol 2017; 153:64-85. https://doi.org/10.1016/j.pneurobio.2017.03.006.

[33]	Shin DW. Dual roles of autophagy and their potential drugs for improving cancer therapeutics. Biomol Ther (Seoul) 2020; 28:503-11. https://doi.org/10.4062/biomolther.2020.155.

[34]	Li Z, Liu F, Zhang L, Cao Y, Shao Y, Wang X, et al. Neuroserpin restores autophagy and promotes functional recovery after acute spinal cord injury in rats. Mol Med Rep 2018; 17:2957-63. https://doi.org/10.3892/mmr.2017.8249.

[35]	Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. J Pathol 2010; 221:3-12. https://doi.org/10.1002/path.2697.

[36]	Li Y, Jones JW, Choi HMC, Sarkar C, Kane MA, Koh EY, et al. cPLA2 activation contributes to lysosomal defects leading to impairment of autophagy after spinal cord injury. Cell Death Dis 2019; 10:531. https://doi.org/10.1038/s41419-019-1764-1.

[37]	Liu S, Li Y, Choi HMC, Sarkar C, Koh EY, Wu J, et al. Lysosomal damage after spinal cord injury causes accumulation of RIPK1 and RIPK3 proteins and potentiation of necroptosis. Cell Death Dis 2018; 9:476. https://doi.org/10.1038/s41419-018-0469-1.

[38]	Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell 2010; 140:313-26. https://doi.org/10.1016/j.cell.2010.01.028.

[39]	Gao X, Li QP, Hao JR, Sun K, Feng H, Guo KJ, et al. Therapeutic effects of exendin-4 on spinal cord injury via restoring autophagy function and decreasing necroptosis in neuron. CNS Neurosci Ther 2024; 30:e14835. https://doi.org/10.1111/cns.14835.

[40]	Zhao T, Di J, Kang Y, Zhang H, Yao S, Liu B, et al. TREM2 impedes recovery after spinal cord injury by regulating microglial lysosomal membrane permeabilization-mediated autophagy. Cell Prolif 2025; 58:e70047. https://doi.org/10.1111/cpr.70047.

[41]	Tang P, Hou H, Zhang L, Lan X, Mao Z, Liu D, et al. Autophagy reduces neuronal damage and promotes locomotor recovery via inhibition of apoptosis after spinal cord injury in rats. Mol Neurobiol 2014; 49:276-87. https://doi.org/10.1007/s12035-013-8518-3.

[42]	Hou H, Zhang L, Zhang L, Tang P. Acute spinal cord injury in rats should target activated autophagy. J Neurosurg Spine 2014; 20:568-77. https://doi.org/10.3171/2014.1.Spine13237.

[43]	Lipinski MM, Wu J, Faden AI, Sarkar C. Function and mechanisms of autophagy in brain and spinal cord trauma. Antioxid Redox Signal 2015; 23:565-77. https://doi.org/10.1089/ars.2015.6306.

[44]	Hao HH, Wang L, Guo ZJ, Bai L, Zhang RP, Shuang WB, et al. Valproic acid reduces autophagy and promotes functional recovery after spinal cord injury in rats. Neurosci Bull 2013; 29:484-92. https://doi.org/10.1007/s12264-013-1355-6.

[45]	Zhang D, Xuan J, Zheng BB, Zhou YL, Lin Y, Wu YS, et al. Metformin improves functional recovery after spinal cord injury via autophagy flux stimulation. Mol Neurobiol 2017; 54:3327-41. https://doi.org/10.1007/s12035-016-9895-1.

[46]	Zhou KL, Zhou YF, Wu K, Tian NF, Wu YS, Wang YL, et al. Stimulation of autophagy promotes functional recovery in diabetic rats with spinal cord injury. Sci Rep 2015; 5:17130. https://doi.org/10.1038/srep17130.

[47]

Xiong Y, Xia Y, Deng J, Yan X, Ke J, Zhan J, et al. Direct peritoneal resuscitation with pyruvate protects the spinal cord and induces autophagy via regulating PHD2 in a rat model of spinal cord ischemia-reperfusion injury. Oxidative Med Cell Longev 2020; 2020:4909103. https://doi.org/10.1155/2020/4909103.

[48]	Wu C, Xu H, Li J, Hu X, Wang X, Huang Y, et al. Baicalein attenuates pyroptosis and endoplasmic reticulum stress following spinal cord ischemia-reperfusion injury via autophagy enhancement. Front Pharmacol 2020; 11:1076. https://doi.org/10.3389/fphar.2020.01076.

[49]	Fang B, Li XQ, Bao NR, Tan WF, Chen FS, Pi XL, et al. Role of autophagy in the bimodal stage after spinal cord ischemia reperfusion injury in rats. Neuroscience 2016; 328:107-16. https://doi.org/10.1016/j.neuroscience.2016.04.019.

[50]	Liu S, Sarkar C, Dinizo M, Faden AI, Koh EY, Lipinski MM, et al. Disrupted autophagy after spinal cord injury is associated with ER stress and neuronal cell death. Cell Death Dis 2015; 6:e1582. https://doi.org/10.1038/cddis.2014.527.

[51]	Wang Y, Zhang H. Regulation of autophagy by mTOR signaling pathway. Adv Exp Med Biol 2019; 1206:67-83. https://doi.org/10.1007/978-981-15-0602-4_3.

[52]	Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of ULK1. Nat Cell Biol 2011; 13:132-41. https://doi.org/10.1038/ncb2152.

[53]	Chen M, Nguyen TN, Ren X, Khuu G, Cook ASI, Zhao Y, et al. Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex. Nat Struct Mol Biol 2025; 32:1596-605. https://doi.org/10.1038/s41594-025-01557-x.

[54]	Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med 2013; 19:983-97. https://doi.org/10.1038/nm.3232.

[55]	Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell 2017; 168:960-76. https://doi.org/10.1016/j.cell.2017.02.004.

[56]	Li Y, Guo Y, Fan Y, Tian H, Li K, Mei X. Melatonin enhances autophagy and reduces apoptosis to promote locomotor recovery in spinal cord injury via the PI3K/AKT/mTOR signaling pathway. Neurochem Res 2019; 44:2007-19. https://doi.org/10.1007/s11064-019-02838-w.

[57]	Wang Z, Zhou L, Zheng X, Chen G, Pan R, Li J, et al. Autophagy protects against PI3K/Akt/mTOR-mediated apoptosis of spinal cord neurons after mechanical injury. Neurosci Lett 2017; 656:158-64. https://doi.org/10.1016/j.neulet.2017.07.036.

[58]	Zhang HY, Wang ZG, Wu FZ, Kong XX, Yang J, Lin BB, et al. Regulation of autophagy and ubiquitinated protein accumulation by bFGF promotes functional recovery and neural protection in a rat model of spinal cord injury. Mol Neurobiol 2013; 48:452-64. https://doi.org/10.1007/s12035-013-8432-8.

[59]	Lin SC, Hardie DG. AMPK: sensing glucose as well as cellular energy status. Cell Metab 2018; 27:299-313. https://doi.org/10.1016/j.cmet.2017.10.009.

[60]	Inoki K, Kim J, Guan KL. AMPK and mTOR in cellular energy homeostasis and drug targets. Annu Rev Pharmacol Toxicol 2012; 52:381-400. https://doi.org/10.1146/annurev-pharmtox-010611-134537.

[61]	Park JM, Lee DH, Kim DH. Redefining the role of AMPK in autophagy and the energy stress response. Nat Commun 2023; 14:2994. https://doi.org/10.1038/s41467-023-38401-z.

[62]	Kim DH. Contrasting views on the role of AMPK in autophagy. Bioessays 2024; 46:e2300211. https://doi.org/10.1002/bies.202300211.

[63]	Lin S, Tian H, Lin J, Xu C, Yuan Y, Gao S, et al. Zinc promotes autophagy and inhibits apoptosis through AMPK/mTOR signaling pathway after spinal cord injury. Neurosci Lett 2020; 736:135263. https://doi.org/10.1016/j.neulet.2020.135263.

[64]	Meng HY, Shao DC, Li H, Huang XD, Yang G, Xu B, et al. Resveratrol improves neurological outcome and neuroinflammation following spinal cord injury through enhancing autophagy involving the AMPK/mTOR pathway. Mol Med Rep 2018; 18:2237-44. https://doi.org/10.3892/mmr.2018.9194.

[65]	Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M, Gennarino VA, et al. A gene network regulating lysosomal biogenesis and function. Science 2009; 325:473-7. https://doi.org/10.1126/science.1174447.

[66]	Roczniak-Ferguson A, Petit CS, Froehlich F, Qian S, Ky J, Angarola B, et al. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci Signal 2012; 5:ra42. https://doi.org/10.1126/scisignal.2002790.

[67]	Martina JA, Chen Y, Gucek M, Puertollano R. mTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy 2012; 8:903-14. https://doi.org/10.4161/auto.19653.

[68]	Chen H, Gong S, Zhang H, Chen Y, Liu Y, Hao J, et al. From the regulatory mechanism of TFEB to its therapeutic implications. Cell Death Discov 2024; 10:84. https://doi.org/10.1038/s41420-024-01850-6.

[69]	Bai L, Mei X, Wang Y, Yuan Y, Bi Y, Li G, et al. The role of netrin-1 in improving functional recovery through autophagy stimulation following spinal cord injury in rats. Front Cell Neurosci 2017; 11:350. https://doi.org/10.3389/fncel.2017.00350.

[70]	Wu C, Chen H, Zhuang R, Zhang H, Wang Y, Hu X, et al. Betulinic acid inhibits pyroptosis in spinal cord injury by augmenting autophagy via the AMPK-mTOR-TFEB signaling pathway. Int J Biol Sci 2021; 17:1138-52. https://doi.org/10.7150/ijbs.57825.

[71]	Tang YJ, Li K, Yang CL, Huang K, Zhou J, Shi Y, et al. Bisperoxovanadium protects against spinal cord injury by regulating autophagy via activation of ERK1/2 signaling. Drug Des Devel Ther 2019; 13:513-21. https://doi.org/10.2147/dddt.S187878.

[72]	Zhu N, Ruan J, Yang X, Huang Y, Jiang Y, Wang Y, et al. Triptolide improves spinal cord injury by promoting autophagy and inhibiting apoptosis. Cell Biol Int 2020; 44:785-94. https://doi.org/10.1002/cbin.11273.

[73]	Li G, Chen T, Zhu Y, Xiao X, Bu J, Huang Z. miR-103 alleviates autophagy and apoptosis by regulating SOX2 in LPS-injured PC12 cells and SCI rats. Iran J Basic Med Sci 2018; 21:292-300. 10.22038/ijbms.2018.25980.6392.

[74]	Zhou M, Xu W, Wang J, Yan J, Shi Y, Zhang C, et al. Boosting mTOR-dependent autophagy via upstream TLR4-MyD88-MAPK signalling and downstream NF-κB pathway quenches intestinal inflammation and oxidative stress injury. EBioMedicine 2018; 35:345-60. https://doi.org/10.1016/j.ebiom.2018.08.035.

[75]	Gupta S, Cassel SL, Sutterwala FS, Dagvadorj J. Regulation of the NLRP3 inflammasome by autophagy and mitophagy. Immunol Rev 2025; 329:e13410. https://doi.org/10.1111/imr.13410.

[76]	Zhong Z, Umemura A, Sanchez-Lopez E, Liang S, Shalapour S, Wong J, et al. NF-κB restricts inflammasome activation via elimination of damaged mitochondria. Cell 2016; 164:896-910. https://doi.org/10.1016/j.cell.2015.12.057.

[77]

Huang Z, Zhou X, Zhang X, Huang L, Sun Y, Cheng Z, et al. Pien-tze-huang, a Chinese patent formula, attenuates NLRP3 inflammasome-related neuroinflammation by enhancing autophagy via the AMPK/mTOR/ULK1 signaling pathway. Biomed Pharmacother 2021; 141:111814. https://doi.org/10.1016/j.biopha.2021.111814.

[78]	Wang C, Wang Q, Lou Y, Xu J, Feng Z, Chen Y, et al. Salidroside attenuates neuroinflammation and improves functional recovery after spinal cord injury through microglia polarization regulation. J Cell Mol Med 2018; 22:1148-66. https://doi.org/10.1111/jcmm.13368.

[79]	Lin JQ, Tian H, Zhao XG, Lin S, Li DY, Liu YY, et al. Zinc provides neuroprotection by regulating NLRP3 inflammasome through autophagy and ubiquitination in a spinal contusion injury model. CNS Neurosci Ther 2021; 27:413-25. https://doi.org/10.1111/cns.13460.

[80]	Zhou J, Li Z, Zhao Q, Wu T, Zhao Q, Cao Y. Knockdown of SNHG1 alleviates autophagy and apoptosis by regulating miR-362-3p/JAK2/STAT3 pathway in LPS-injured PC12 cells. Neurochem Res 2021; 46:945-56. https://doi.org/10.1007/s11064-020-03224-7.

[81]	Lee Y, Chou TF, Pittman SK, Keith AL, Razani B, Weihl CC. Keap1/Cullin3 modulates p62/SQSTM1 activity via UBA domain ubiquitination. Cell Rep 2017; 19:188-202. https://doi.org/10.1016/j.celrep.2017.03.030.

[82]	Shan C, Wang Y, Wang Y. The crosstalk between autophagy and Nrf2 signaling in cancer: from biology to clinical applications. Int J Biol Sci 2024; 20:6181-206. https://doi.org/10.7150/ijbs.103187.

[83]	Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y, et al. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol 2010; 12:213-23. https://doi.org/10.1038/ncb2021.

[84]	Ko SH, Apple EC, Liu Z, Chen L. Age-dependent autophagy induction after injury promotes axon regeneration by limiting NOTCH. Autophagy 2020; 16:2052-68. https://doi.org/10.1080/15548627.2020.1713645.

[85]	Herb M, Schramm M. Functions of ROS in macrophages and antimicrobial immunity. Antioxidants (Basel) 2021; 10:313. https://doi.org/10.3390/antiox10020313.

[86]	Hawkins CL, Davies MJ. Detection, identification, and quantification of oxidative protein modifications. J Biol Chem 2019; 294:19683-708. https://doi.org/10.1074/jbc.REV119.006217.

[87]	Cooney SJ, Zhao Y, Byrnes KR. Characterization of the expression and inflammatory activity of NADPH oxidase after spinal cord injury. Free Radic Res 2014; 48:929-39. https://doi.org/10.3109/10715762.2014.927578.

[88]	Sullivan PG, Krishnamurthy S, Patel SP, Pandya JD, Rabchevsky AG. Temporal characterization of mitochondrial bioenergetics after spinal cord injury. J Neurotrauma 2007; 24:991-9. https://doi.org/10.1089/neu.2006.0242.

[89]	Zmijewski JW, Banerjee S, Bae H, Friggeri A, Lazarowski ER, Abraham E. Exposure to hydrogen peroxide induces oxidation and activation of AMP-activated protein kinase. J Biol Chem 2010; 285:33154-64. https://doi.org/10.1074/jbc.M110.143685.

[90]

He JL, Dong XH, Li ZH, Wang XY, Fu ZA, Shen N. Pterostilbene inhibits reactive oxygen species production and apoptosis in primary spinal cord neurons by activating autophagy via the mechanistic target of rapamycin signaling pathway. Mol Med Rep 2018; 17:4406-14. https://doi.org/10.3892/mmr.2018.8412.

[91]	Zhang H, Wu C, Yu DD, Su H, Chen Y, Ni W. Piperine attenuates the inflammation, oxidative stress, and pyroptosis to facilitate recovery from spinal cord injury via autophagy enhancement. Phytother Res 2023; 37:438-51. https://doi.org/10.1002/ptr.7625.

[92]

Zhang T, Wu P, Budbazar E, Zhu Q, Sun C, Mo J, et al. Mitophagy reduces oxidative stress via Keap1 (kelch-like epichlorohydrin-associated protein 1)/Nrf2 (nuclear factor-E2-related factor 2)/PHB2 (prohibitin 2) pathway after subarachnoid hemorrhage in rats. Stroke 2019; 50:978-88. https://doi.org/10.1161/strokeaha.118.021590.

[93]	Dinkova-Kostova AT, Abramov AY. The emerging role of Nrf2 in mitochondrial function. Free Radic Biol Med 2015;88:179-88. https://doi.org/10.1016/j.freeradbiomed.2015.04.036.

[94]	Zhang L, Wang H. Targeting the NF-E2-related factor 2 pathway: a novel strategy for traumatic brain injury. Mol Neurobiol 2018; 55:1773-85. https://doi.org/10.1007/s12035-017-0456-z.

[95]	Liu H, Zhang J, Xu X, Lu S, Yang D, Xie C, et al. SARM1 promotes neuroinflammation and inhibits neural regeneration after spinal cord injury through NF-κB signaling. Theranostics 2021; 11:4187-206. https://doi.org/10.7150/thno.49054.

[96]	Lukacova N, Kisucka A, Kiss Bimbova K, Bacova M, Ileninova M, Kuruc T, et al. Glial-neuronal interactions in pathogenesis and treatment of spinal cord injury. Int J Mol Sci 2021; 22:13577. https://doi.org/10.3390/ijms222413577.

[97]	Wang R, Niu Z, Tian R, Chen A, Liao H, Kuang R, et al. The role of autophagy in spinal cord injury: mechanisms, crosstalk, and therapeutic strategies. Neural Regen Res 2026; 21:2110-24. https://doi.org/10.4103/nrr.Nrr-d-24-01467.

[98]	Elmalky MI, Alvarez-Bolado G, Younsi A, Skutella T. Axonal regeneration after spinal cord injury: molecular mechanisms, regulatory pathways, and novel strategies. Biology (Basel) 2024; 13:703. https://doi.org/10.3390/biology13090703.

[99]	Dogterom M, Koenderink GH. Actin-microtubule crosstalk in cell biology. Nat Rev Mol Cell Biol 2019; 20:38-54. https://doi.org/10.1038/s41580-018-0067-1.

[100]

Wu J, Akhmanova A. Microtubule-organizing centers. Annu Rev Cell Dev Biol 2017; 33:51-75. https://doi.org/10.1146/annurev-cellbio-100616-060615.

[101]

Lei WL, Xing SG, Deng CY, Ju XC, Jiang XY, Luo ZG. Laminin/β1 integrin signal triggers axon formation by promoting microtubule assembly and stabilization. Cell Res 2012; 22:954-72. https://doi.org/10.1038/cr.2012.40.

[102]

Hellal F, Hurtado A, Ruschel J, Flynn KC, Laskowski CJ, Umlauf M, et al. Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury. Science 2011; 331:928-31. https://doi.org/10.1126/science.1201148.

[103]

Wang Q, Zhang H, Xu H, Zhao Y, Li Z, Li J, et al. Novel multi-drug delivery hydrogel using scar-homing liposomes improves spinal cord injury repair. Theranostics 2018; 8:4429-46. https://doi.org/10.7150/thno.26717.

[104]

Ruschel J, Hellal F, Flynn KC, Dupraz S, Elliott DA, Tedeschi A, et al. Axonal regeneration. Systemic administration of epothilone B promotes axon regeneration after spinal cord injury. Science 2015; 348:347-52. https://doi.org/10.1126/science.aaa2958.

[105]

Kononenko NL, Claßen GA, Kuijpers M, Puchkov D, Maritzen T, Tempes A, et al. Retrograde transport of TrkB-containing autophagosomes via the adaptor AP-2 mediates neuronal complexity and prevents neurodegeneration. Nat Commun 2017; 8:14819. https://doi.org/10.1038/ncomms14819.

[106]

Pan D, Zhu S, Zhang W, Wei Z, Yang F, Guo Z, et al. Autophagy induced by Schwann cell-derived exosomes promotes recovery after spinal cord injury in rats. Biotechnol Lett 2022; 44:129-42. https://doi.org/10.1007/s10529-021-03198-8.

[107]

Chen J, Wang Z, Mao Y, Zheng Z, Chen Y, Khor S, et al. Liraglutide activates autophagy via GLP-1R to improve functional recovery after spinal cord injury. Oncotarget 2017; 8:85949-68. 10.18632/oncotarget.20791.

[108]

He M, Ding Y, Chu C, Tang J, Xiao Q, Luo ZG. Autophagy induction stabilizes microtubules and promotes axon regeneration after spinal cord injury. Proc Natl Acad Sci U S A 2016; 113:11324-9. https://doi.org/10.1073/pnas.1611282113.

[109]

Grenningloh G, Soehrman S, Bondallaz P, Ruchti E, Cadas H. Role of the microtubule destabilizing proteins SCG10 and stathmin in neuronal growth. J Neurobiol 2004; 58:60-9. https://doi.org/10.1002/neu.10279.

[110]

Su M, Guan H, Zhang F, Gao Y, Teng X, Yang W. HDAC6 regulates the chaperone-mediated autophagy to prevent oxidative damage in injured neurons after experimental spinal cord injury. Oxidative Med Cell Longev 2016; 2016:7263736. https://doi.org/10.1155/2016/7263736.

[111]

Banerjee R, Beal MF, Thomas B. Autophagy in neurodegenerative disorders: pathogenic roles and therapeutic implications. Trends Neurosci 2010; 33:541-9. https://doi.org/10.1016/j.tins.2010.09.001.

[112]

Maday S, Holzbaur EL. Autophagosome biogenesis in primary neurons follows an ordered and spatially regulated pathway. Dev Cell 2014; 30:71-85. https://doi.org/10.1016/j.devcel.2014.06.001.

[113]

Stavoe AKH, Holzbaur ELF. Autophagy in neurons. Annu Rev Cell Dev Biol 2019; 35:477-500. https://doi.org/10.1146/annurev-cellbio-100818-125242.

[114]

Pickrell AM, Youle RJ. The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson’s disease. Neuron 2015; 85:257-73. https://doi.org/10.1016/j.neuron.2014.12.007.

[115]

Fang EF, Hou Y, Palikaras K, Adriaanse BA, Kerr JS, Yang B, et al. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat Neurosci 2019; 22:401-12. https://doi.org/10.1038/s41593-018-0332-9.

[116]

Springer JE, Azbill RD, Knapp PE. Activation of the caspase-3 apoptotic cascade in traumatic spinal cord injury. Nat Med 1999; 5:943-6. https://doi.org/10.1038/11387.

[117]

Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 2012; 13:251-62. https://doi.org/10.1038/nrm3311.

[118]

Li X, Zhu M, Xiao L, Li J, Yu K, Zhang Q, et al. Extracellular vesicles derived from Schwann cells to enhance bone and dental tissue regeneration: a literature review. J Nanobiotechnology 2025; 23:502. https://doi.org/10.1186/s12951-025-03585-7.

[119]

Xu B, Zhou Z, Fang J, Wang J, Tao K, Liu J, et al. Exosomes derived from Schwann cells alleviate mitochondrial dysfunction and necroptosis after spinal cord injury via AMPK signaling pathway-mediated mitophagy. Free Radic Biol Med 2023; 208:319-33. https://doi.org/10.1016/j.freeradbiomed.2023.08.026.

[120]

Rong Y, Liu W, Wang J, Fan J, Luo Y, Li L, et al. Neural stem cell-derived small extracellular vesicles attenuate apoptosis and neuroinflammation after traumatic spinal cord injury by activating autophagy. Cell Death Dis 2019; 10:340. https://doi.org/10.1038/s41419-019-1571-8.

[121]

Goldshmit Y, Kanner S, Zacs M, Frisca F, Pinto AR, Currie PD, et al. Rapamycin increases neuronal survival, reduces inflammation and astrocyte proliferation after spinal cord injury. Mol Cell Neurosci 2015; 68:82-91. https://doi.org/10.1016/j.mcn.2015.04.006.

[122]

Shi Q, Wu Y, Zhang B, Wu S, Wang X, Lin F, et al. Progranulin promotes functional recovery in rats with acute spinal cord injury via autophagy-induced anti-inflammatory microglial polarization. Mol Neurobiol 2022; 59:4304-14. https://doi.org/10.1007/s12035-022-02836-0.

[123]

Zendedel A, Johann S, Mehrabi S, Joghataei MT, Hassanzadeh G, Kipp M, et al. Activation and regulation of NLRP3 inflammasome by intrathecal application of SDF-1α in a spinal cord injury model. Mol Neurobiol 2016; 53:3063-75. https://doi.org/10.1007/s12035-015-9203-5.

[124]

Ma SF, Chen YJ, Zhang JX, Shen L, Wang R, Zhou JS, et al. Adoptive transfer of M2 macrophages promotes locomotor recovery in adult rats after spinal cord injury. Brain Behav Immun 2015; 45:157-70. https://doi.org/10.1016/j.bbi.2014.11.007.

[125]

Xue S, Cao ZX, Wang JN, Zhao QX, Han J, Yang WJ, et al. Receptor-interacting protein kinase 3 inhibition relieves mechanical allodynia and suppresses NLRP3 inflammasome and NF-κB in a rat model of spinal cord injury. Front Mol Neurosci 2022; 15:861312. https://doi.org/10.3389/fnmol.2022.861312.

[126]

Mi J, Yang Y, Yao H, Huan Z, Xu C, Ren Z, et al. Inhibition of heat shock protein family a member 8 attenuates spinal cord ischemia-reperfusion injury via astrocyte NF-κB/NLRP3 inflammasome pathway: HSPA8 inhibition protects spinal ischemia-reperfusion injury. J Neuroinflammation 2021; 18:170. https://doi.org/10.1186/s12974-021-02220-0.

[127]

Jiang F, Xia M, Zhang Y, Chang J, Cao J, Zhang Z, et al. Cannabinoid receptor-2 attenuates neuroinflammation by promoting autophagy-mediated degradation of the NLRP3 inflammasome post spinal cord injury. Front Immunol 2022; 13:993168. https://doi.org/10.3389/fimmu.2022.993168.

[128]

Lv B, Shen N, Cheng Z, Chen Y, Ding H, Yuan J, et al. Strategies for biomaterial-based spinal cord injury repair via the TLR4-NF-κB signaling pathway. Front Bioeng Biotechnol 2021; 9:813169. https://doi.org/10.3389/fbioe.2021.813169.

[129]

Xiao G. Autophagy and NF-kappaB: fight for fate. Cytokine Growth Factor Rev 2007; 18:233-43. https://doi.org/10.1016/j.cytogfr.2007.04.006.

[130]

Mi B, Wang J, Liu Y, Liu J, Hu L, Panayi AC, et al. Icariin activates autophagy via down-regulation of the NF-κB signaling-mediated apoptosis in chondrocytes. Front Pharmacol 2018; 9:605. https://doi.org/10.3389/fphar.2018.00605.

[131]

Guo Y, Liu S, Zhang X, Wang L, Gao J, Han A, et al. G-CSF promotes autophagy and reduces neural tissue damage after spinal cord injury in mice. Lab Invest 2015; 95:1439-49. https://doi.org/10.1038/labinvest.2015.120.

[132]

Williams-Bey Y, Boularan C, Vural A, Huang NN, Hwang IY, Shan-Shi C, et al. Omega-3 free fatty acids suppress macrophage inflammasome activation by inhibiting NF-κB activation and enhancing autophagy. PLoS One 2014; 9:e97957. https://doi.org/10.1371/journal.pone.0097957.

[133]

Zhang B, Lin F, Dong J, Liu J, Ding Z, Xu J. Peripheral macrophage-derived exosomes promote repair after spinal cord injury by inducing local anti-inflammatory type microglial polarization via increasing autophagy. Int J Biol Sci 2021; 17:1339-52. https://doi.org/10.7150/ijbs.54302.

[134]

Yang J, Dong J, Li H, Gong Z, Wang B, Du K, et al. Circular RNA HIPK2 promotes A1 astrocyte activation after spinal cord injury through autophagy and endoplasmic reticulum stress by modulating miR-124-3p-mediated Smad2 repression. ACS Omega 2024; 9:781-97. https://doi.org/10.1021/acsomega.3c06679.

[135]

Belgrad J, De Pace R, Fields RD . Autophagy in myelinating glia. J Neurosci 2020; 40:256-66. https://doi.org/10.1523/jneurosci.1066-19.2019.

[136]

Aber ER, Griffey CJ, Davies T, Li AM, Yang YJ, Croce KR, et al. Oligodendroglial macroautophagy is essential for myelin sheath turnover to prevent neurodegeneration and death. Cell Rep 2022; 41:111480. https://doi.org/10.1016/j.celrep.2022.111480.

[137]

Chen HC, Fong TH, Hsu PW, Chiu WT. Multifaceted effects of rapamycin on functional recovery after spinal cord injury in rats through autophagy promotion, anti-inflammation, and neuroprotection. J Surg Res 2013; 179:e203-10. https://doi.org/10.1016/j.jss.2012.02.023.

[138]

Wang H, Wang Y, Li D, Liu Z, Zhao Z, Han D, et al. VEGF inhibits the inflammation in spinal cord injury through activation of autophagy. Biochem Biophys Res Commun 2015; 464:453-8. https://doi.org/10.1016/j.bbrc.2015.06.146.

[139]

Chen G, Li J, Wang Z, Liu W. Ezetimibe protects against spinal cord injury by regulating autophagy and apoptosis through inactivation of PI3K/AKT/mTOR signaling. Am J Transl Res 2020; 12:2685-94.

[140]

Gao K, Niu J, Dang X. Neuroprotection of melatonin on spinal cord injury by activating autophagy and inhibiting apoptosis via SIRT1/AMPK signaling pathway. Biotechnol Lett 2020; 42:2059-69. https://doi.org/10.1007/s10529-020-02939-5.

[141]

Ding K, Xu J, Wang H, Zhang L, Wu Y, Li T. Melatonin protects the brain from apoptosis by enhancement of autophagy after traumatic brain injury in mice. Neurochem Int 2015; 91:46-54. https://doi.org/10.1016/j.neuint.2015.10.008.

[142]

Sun X, Wang D, Zhang T, Lu X, Duan F, Ju L, et al. Eugenol attenuates cerebral ischemia-reperfusion injury by enhancing autophagy via AMPK-mTOR-p70S6K pathway. Front Pharmacol 2020; 11:84. https://doi.org/10.3389/fphar.2020.00084.

[143]

Forouzanfar F, Read MI, Barreto GE, Sahebkar A. Neuroprotective effects of curcumin through autophagy modulation. IUBMB Life 2020; 72:652-64. https://doi.org/10.1002/iub.2209.

[144]

Bisicchia E, Latini L, Cavallucci V, Sasso V, Nicolin V, Molinari M, et al. Autophagy inhibition favors survival of rubrospinal neurons after spinal cord hemisection. Mol Neurobiol 2017; 54:4896-907. https://doi.org/10.1007/s12035-016-0031-z.

[145]

Wu F, Wei X, Wu Y, Kong X, Hu A, Tong S, et al. Chloroquine promotes the recovery of acute spinal cord injury by inhibiting autophagy-associated inflammation and endoplasmic reticulum stress. J Neurotrauma 2018; 35:1329-44. https://doi.org/10.1089/neu.2017.5414.

[146]

Gong L, Yin J, Zhang Y, Huang R, Lou Y, Jiang H, et al. Neuroprotective mechanisms of ginsenoside Rb1 in central nervous system diseases. Front Pharmacol 2022; 13:914352. https://doi.org/10.3389/fphar.2022.914352.

[147]

Li L, Jiang HK, Li YP, Guo YP. Hydrogen sulfide protects spinal cord and induces autophagy via miR-30c in a rat model of spinal cord ischemia-reperfusion injury. J Biomed Sci 2015; 22:50. https://doi.org/10.1186/s12929-015-0135-1.

[148]

Xie L, Yu S, Yang K, Li C, Liang Y. Hydrogen sulfide inhibits autophagic neuronal cell death by reducing oxidative stress in spinal cord ischemia reperfusion injury. Oxidative Med Cell Longev 2017; 2017:8640284. https://doi.org/10.1155/2017/8640284.

[149]

Gao K, Niu J, Dang X. Wnt-3a improves functional recovery through autophagy activation via inhibiting the mTOR signaling pathway after spinal cord injury. Neurosci Lett 2020; 737:135305. https://doi.org/10.1016/j.neulet.2020.135305.

[150]

Zhang JY, Lee JH, Gu X, Wei ZZ, Harris MJ, Yu SP, et al. Intranasally delivered Wnt3a improves functional recovery after traumatic brain injury by modulating autophagic, apoptotic, and regenerative pathways in the mouse brain. J Neurotrauma 2018; 35:802-13. https://doi.org/10.1089/neu.2016.4871.

[151]

Wang X, Zhou Z, Zhang Y, Liu J, Qin T, Zhou W, et al. Exosome-shuttled miR-5121 from A2 astrocytes promotes BSCB repair after traumatic SCI by activating autophagy in vascular endothelial cells. J Nanobiotechnology 2025; 23:291. https://doi.org/10.1186/s12951-025-03365-3.

[152]

Chen J, He Q, Xie H, Gu B, Zhou L, Jiang D, et al. Autophagy modulation by hADSCs and green light therapy alleviates inflammation and promotes functional recovery after spinal cord injury. Stem Cell Res Ther 2025; 16:256. https://doi.org/10.1186/s13287-025-04367-6.