CoChat
Sign Up
Cited by 3Pain Mechanisms and TreatmentsPain Management and TreatmentIon Channels and Receptors

SGK1-HDAC4-HMGB1 signaling pathway in the spinal cord dorsal horn participates in diabetic neuropathic pain

Open access
Zhang, Mao-Biao, Chen, Jia-Li, Lu, Jia-Hui, Jia, Gai-Li, Cao, Hong, Li, Jun·2025·Molecular Pain
DOI 10.1177/17448069251321143PMC PMC11837076
Open this paper in CoChat — free account

Abstract

Purpose: This study aimed to determine whether serum-and glucocorticoid-inducible kinase1 (SGK1) activation-dependent histone deacetylase 4 (HDAC4) phosphorylation, nucleocytoplasmic trafficking, and subsequent regulation of high-mobility group protein box 1 (HMGB1) expression are involved in type 2 diabetic neuropathic pain (DNP). Methods: The type 2 diabetic neuropathic pain model was established in rats by feeding them with a high-fat and high-sugar diet for 8 weeks and then fasting them for 12 h, followed by a single intraperitoneal injection of streptozotocin (STZ, 35 mg/kg). SGK1 was inhibited in the spinal cord by intrathecal administration of the SGK1 inhibitor GSK-650394. Results: The present study revealed that pSGK1/tSGK1 was persistently upregulated in the spinal cord of rats with type-2 DNP. The downregulation of pSGK1/tSGK1 through the intrathecal injection of the SGK1 inhibitor GSK-650394 significantly ameliorated the pain hypersensitivity, relieved the abnormal expression of pHDAC4/tHDAC4 and HMGB1, and affected HDAC4 nucleocytoplasmic trafficking in DNP rats. Conclusion: Our data suggest that SGK1 in the spinal cord modulates type-2 DNP by regulating the HDAC4/HMGB1 pathway.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1177/17448069251321143

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • SGK1 phosphorylates HDAC4 to regulate epigenetic control in the transcription of many genes.

    “SGK1 also phosphorylates HDAC4 to regulate epigenetic control in the transcription of many genes [52].”

    From Elevated SGK1 increases Tau phosphorylation and microtubule instability in Alzheimer’s patient-derived cortical neurons (2026) · cites this paper as [52]

    The Introduction says SGK1 acts through HDAC4 phosphorylation and that HDAC4’s resulting movement between the nucleus and cytoplasm is a mechanism regulating gene transcription. The Discussion links HDAC4-associated epigenetic modification to altered HMGB1 expression, but does not establish that this SGK1–HDAC4 pathway controls transcription of many genes. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 42

  1. [1]Harreiter J Roden M. Diabetes mellitus: definition, classification, diagnosis, screening and prevention (Update 2023). Wien Klin Wochenschr 2023; 135: 7– 17. 37101021 PMC10133036
  2. [2]Chen L Wang H Xing J Shi X Huang H Huang J Xu C. Silencing P2X7R alleviates diabetic neuropathic pain involving TRPV1 via PKCε/P38MAPK/NF-κB signaling pathway in rats. Int J Mol Sci 2022; 23(22): 14141. 36430617 PMC9696864
  3. [3]Zhou C-H Zhang M-X Zhou S-S Li H Gao J Du L Yin X-X. SIRT1 attenuates neuropathic pain by epigenetic regulation of mGluR1/5 expressions in type 2 diabetic rats. Pain 2017; 158: 130– 139. 27749604
  4. [4]Jiang W Zhang L Tan X Yu P Dong M. Inflammation and histone modification in chronic pain. Front Immunol 2022; 13: 1087648. 36713369 PMC9880030
  5. [6]Zhang L Chen C Qi J. Activation of HDAC4 and GR signaling contributes to stress-induced hyperalgesia in the medial prefrontal cortex of rats. Brain Res 2020; 1747: 147051. 32783961
  6. [7]Dai X Lin A Zhuang L Zeng Q Cai L Wei Y Liang H Gao W Zhang J Chen X. Targeting SIK3 to modulate hippocampal synaptic plasticity and cognitive function by regulating the transcription of HDAC4 in a mouse model of Alzheimer’s disease. Neuropsychopharmacology 2023; 49(6): 942– 952. 38057370 PMC11039747
  7. [8]Lin T-B Hsieh M-C Lai C-Y Cheng J-K Chau Y-P Ruan T Chen G-D Peng H-Y. Modulation of nerve injury-induced HDAC4 cytoplasmic retention contributes to neuropathic pain in rats. Anesthesiology 2015; 123: 199– 212. 25871743
  8. [9]Colussi C Aceto G Ripoli C Bertozzi A Li Puma D Paccosi E D’Ascenzo M Grassi C. Cytoplasmic HDAC4 recovers synaptic function in the 3×Tg mouse model of Alzheimer’s disease. Neuropathol Appl Neurobiol 2023; 49: e12861. PMC10099707 36331820
  9. [10]Xiao L Han X Wang X Li Q Shen P Liu Z Cui Y Chen Y. Spinal Serum- and Glucocorticoid-Regulated Kinase 1 (SGK1) signaling contributes to morphine-induced analgesic tolerance in rats. Neuroscience 2019; 413: 206– 218. 31220544
  10. [11]Wang X Liu Q. Dexmedetomidine relieved neuropathic pain and inflammation response induced by CCI through HMGB1/TLR4/NF-κB signal pathway. Biol Pharm Bull. Epub ahead of print 20 August 2021. DOI: 10.1248/bpb.b21-00329. 34421084 · DOI
  11. [12]Lin T-B Hsieh M-C Lai C-Y Cheng J-K Wang H-H Chau Y-P Chen G-D Peng H-Y. Melatonin relieves neuropathic allodynia through spinal MT2-enhanced PP2Ac and downstream HDAC4 shuttling-dependent epigenetic modification of hmgb1 transcription. J Pineal Res 2016; 60: 263– 276. 26732138
  12. [13]Dang J Wu Y Cao H Meng B Huang C Chen G Li J Song X Lian Q. Establishment of a rat model of type II diabetic neuropathic pain. Pain Med 2014; 15: 637– 646. 24716590
  13. [14]Muniyappa R Lee S Chen H Quon MJ. Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab 2007; 294: E15–E26. 17957034
  14. [15]Wang J Ye X Wei N Wu S Zhang Z Luo G Li X Li J Cao H. Reactive oxygen species contributes to type 2 diabetic neuropathic pain via the thioredoxin-interacting protein-NOD-like receptor protein 3- N -Methyl-D-Aspartic acid receptor 2B pathway. Anesth Analg 2022; 135: 865– 876. 35819160 PMC9444295
  15. [16]Zhu Y-B Jia G-L Wang J-W Ye X-Y Lu J-H Chen J-L Zhang M-B Xie C-S Shen Y-J Tao Y-X Li J Cao H. Activation of CaMKII and GluR1 by the PSD-95-GluN2B coupling-dependent phosphorylation of GluN2B in the spinal cord in a rat model of type-2 diabetic neuropathic pain. J Neuropathol Exp Neurol 2020; 79(7): 800– 808. 32386416
  16. [17]Jia G-L Huang Q Cao Y-N Xie C-S Shen Y-J Chen J-L Lu J-H Zhang M-B Li J Tao Y-X Cao H. Cav-1 participates in the development of diabetic neuropathy pain through the TLR4 signaling pathway. J Cell Physiol 2019; 235: 2060– 2070. 31318049
  17. [18]Chen J-L Lu J-H Xie C-S Shen Y-J Wang J-W Ye X-Y Zhang M-B Jia G-L Tao Y-X Li J Cao H. Caveolin-1 in spinal cord modulates type-2 diabetic neuropathic pain through the Rac1/NOX2/NR2B signaling pathway. Am J Transl Res 2020; 12(5): 1714– 1727. 32509171 PMC7269978
  18. [19]Li C-D Zhao J-Y Chen J-L Lu J-H Zhang M-B Huang Q Cao Y-N Jia G-L Tao Y-X Li J Cao H. Mechanism of the JAK2/STAT3-CAV-1-NR2B signaling pathway in painful diabetic neuropathy. Endocrine 2019; 64(1): 55– 66. 30830585 PMC6453875
  19. [20]Li K Zhao G-Q Li L-Y Wu G-Z Cui S-s. Epigenetic upregulation of Cdk5 in the dorsal horn contributes to neuropathic pain in rats. Neuroreport 2014; 25(14): 1116– 1121. 25055140
  20. [21]Liang L Tao Y-X. Expression of acetyl-histone H3 and acetyl-histone H4 in dorsal root ganglion and spinal dorsal horn in rat chronic pain models. Life Sci 2018; 211: 182– 188. 30236868
  21. [22]Wang X Shen X Xu Y Xu S Xia F Zhu B Liu Y Wang W Wu H Wang F. The etiological changes of acetylation in peripheral nerve injury-induced neuropathic hypersensitivity. Mol Pain 2018; 14: 17448069. PMC6144590 30105933
  22. [23]Borgonetti V Meacci E Pierucci F Romanelli MN Galeotti N. Dual HDAC/BRD4 inhibitors relieves neuropathic pain by attenuating inflammatory response in microglia after spared nerve injury. Neurotherapeutics 2022; 19(5): 1634– 1648. 35501470 PMC9606187
  23. [24]Cui S-S Lu R Zhang H Wang W Ke J-J. Suberoylanilide hydroxamic acid prevents downregulation of spinal glutamate transporter-1 and attenuates spinal nerve ligation-induced neuropathic pain behavior. Neuroreport 2016; 27: 427– 434. 26953753
  24. [25]Denk F Huang W Sidders B Bithell A Crow M Grist J Sharma S Ziemek D Rice AS Buckley NJ McMahon SB. HDAC inhibitors attenuate the development of hypersensitivity in models of neuropathic pain. Pain 2013; 154: 1668– 1679. 23693161 PMC3763368
  25. [26]Kukkar A Singh N Jaggi AS. Attenuation of neuropathic pain by sodium butyrate in an experimental model of chronic constriction injury in rats. J Formos Med Assoc 2014; 113: 921– 928. 23870713
  26. [27]Tao W Zhou W Wang Y Sun T Wang H Zhang Z Jin Y. Histone deacetylase inhibitor-induced emergence of synaptic delta-opioid receptors and behavioral antinociception in persistent neuropathic pain. Neuroscience 2016; 339: 54– 63. 27646288
  27. [28]Peng H-Y Chen G-D Hsieh M-C Lai C-Y Huang Y-P Lin T-B. Spinal SGK1/GRASP-1/Rab4 is involved in complete Freund’s adjuvant-induced inflammatory pain via regulating dorsal horn GluR1-containing AMPA receptor trafficking in rats. Pain 2012; 153: 2380– 2392. 22980744
  28. [29]Zhang M Chen H Liu M Zhu K Hao Y Zhu D Li P. Serum- and glucocorticoid-inducible kinase 1 promotes insulin resistance in adipocytes via degradation of insulin receptor substrate 1. Diabetes Metab Res Rev 2021; 37: e3451. 33724645
  29. [30]Zhou B Zhang Y Li S Wu L Fejes-Toth G Naray-Fejes-Toth A Soukas A. Serum- and glucocorticoid-induced kinase drives hepatic insulin resistance by directly inhibiting AMP-activated protein kinase. Cell Rep 2021; 37: 109785. 34610303 PMC8576737
  30. [31]Ma Y Tsai M Hsu W Lee E. SGK protein kinase facilitates the expression of long-term potentiation in hippocampal neurons. Learn Mem 2006; 13: 114– 118. 16585788
  31. [32]Zhang Z Wu H Liu Y Gu X Zhang W Ma Z. The GCs-SGK1-ATP signaling pathway in spinal astrocytes underlied presurgical anxiety-induced postsurgical hyperalgesia. Anesth Analg 2019; 129: 1163– 1169. 30113397
  32. [33]Main P Tan W Wheeler D Fitzsimons H. Increased abundance of nuclear HDAC4 impairs neuronal development and long-term memory. Front Mol Neurosci 2021; 14: 616642. 33859551 PMC8042284
  33. [34]Wu Q Yang X Zhang L Zhang Y Feng L. Nuclear accumulation of histone deacetylase 4 (HDAC4) exerts neurotoxicity in models of Parkinson’s disease. Mol Neurobiol 2017; 54(9): 6970– 6983. 27785754
  34. [35]Wu Y Hou F Wang X Kong Q Han X Bai B. Aberrant expression of histone deacetylases 4 in cognitive disorders: molecular mechanisms and a potential target. Front Mol Neurosci 2016; 9: 114. 27847464 PMC5088184
  35. [36]Lai C-Y Hsieh M-C Ho Y-C Chen G-D Chou D Ruan T Lee A-S Wang H-H Chau Y-P Peng H-Y Lai C-H. GluN2B/CaMKII mediates CFA-induced hyperalgesia via HDAC4-modified spinal COX2 transcription. Neuropharmacology 2018; 135: 536– 546. 29614314
  36. [37]Crow M Khovanov N Kelleher JH Sharma S Grant AD Bogdanov Y Wood JN McMahon SB Denk F. HDAC4 is required for inflammation-associated thermal hypersensitivity. FASEB J 2015; 29: 3370– 3378. 25903105 PMC4511203
  37. [38]Cho HM Seok YM Lee HA Song M Kim I. Repression of transcriptional activity of forkhead box O1 by histone deacetylase inhibitors ameliorates hyperglycemia in type 2 diabetic rats. Int J Mol Sci 2018; 19(11): 3539. 30424007 PMC6274985
  38. [39]Tung C-W Hsu Y-C Shih Y-H Chang P-J Lin C-L. Glomerular mesangial cell and podocyte injuries in diabetic nephropathy. Nephrology (Carlton) 2018; 4: 32– 37. 30298646
  39. [40]Zou G Zhong W Wu F Wang X Liu L. Catalpol attenuates cardiomyocyte apoptosis in diabetic cardiomyopathy via Neat1/miR-140-5p/HDAC4 axis. Biochimie 2019; 165: 90– 99. 31078585
  40. [41]Xu Y Li H Chen G Zhu L Lin H Huang C Wei S Yang T Qian W Li X Zhao S Pan W. Radix polygoni multiflori protects against hippocampal neuronal apoptosis in diabetic encephalopathy by inhibiting the HDAC4/JNK pathway. Biomed Pharmacother 2022; 153: 113427. 36076547
  41. [42]McKinsey T Zhang C Olson E. Identification of a signal-responsive nuclear export sequence in class II histone deacetylases. Mol Cell Biol 2001; 21: 6312– 6321. 11509672 PMC87361
  42. [43]Li M Jiang H Gu K Sun X Gu J Li C Wang G. Lidocaine alleviates neuropathic pain and neuroinflammation by inhibiting HMGB1 expression to mediate MIP-1α/CCR1 pathway. J Neuroimmune Pharmacol 2020; 16(2): 318– 333. 32301050

Cited by

Sorted by citations

Authors
Zhang, M.-B., Chen, J.-L., Lu, J.-H., Jia, G.-L., Cao, H., & Li, J.
Affiliations
  • Wenzhou Medical University (CN)
  • Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Corresponding author
Li, Jun
ORCID
Venue
Molecular Pain
Publisher
SAGE Publications
Published
2025-01
Volume
21
Pages
17448069251321143-17448069251321143
ISSN
1744-8069 (ISSN-L)
DOI
10.1177/17448069251321143
PMC
PMC11837076
OpenAlex
W4407275882
Cited by
3
References
1
Citations by year
2026: 1 · 2025: 2
FWCI
1.92
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Pain (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Scientific Research Foundation of Wenzhou (Y20240723)
  • National Natural Science Foundation of China (81771487)
Topics
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
  • Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Keywords
SGK1, HDAC4, HMGB1, diabetic neuropathic pain, type 2 diabetes, dorsal horn, nucleocytoplasmic trafficking, streptozotocin-induced diabetes, hyperalgesia, histone deacetylase
MeSH terms
Serum-Glucocorticoid Regulated Kinases, Animals, Diabetes Mellitus, Experimental, Diabetic Neuropathies, Histone Deacetylases, Male, Neuralgia, Phosphorylation, Signal Transduction, Rats, Sprague-Dawley, Protein Serine-Threonine Kinases, Immediate-Early Proteins, HMGB1 Protein, Rats, Spinal Cord Dorsal Horn

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review