Comprehensive Analysis of Core Genes, Key Pathways, and Immune Infiltration in Intervertebral Disc Degeneration Using Machine Learning and Experimental Validation
Abstract
This study integrated and analyzed two sets of gene expression data related to intervertebral disc degeneration (IVDD) to elucidate its key molecular mechanisms.
Through screening and enrichment analysis of differentially expressed genes (DEGs), 112 DEGs were identified, primarily involved in extracellular matrix remodeling, cytoplasmic translation, and signaling pathways such as PI3K-Akt.
A protein-protein interaction network combined with LASSO and SVM-RFE machine learning algorithms identified 13 hub genes. Immune infiltration analysis revealed reduced infiltration of suppressor cells and monocytes in IVDD samples. In an IL-1β-induced human nucleus pulposus cell degeneration model, qPCR and Western blot experiments confirmed significant downregulation of ADM, ITGB5, RTN4, SLPI, and CSNK1E expression.
This study systematically reveals the potential molecular networks and immune characteristics of IVDD, providing new candidate biomarkers and therapeutic insights for subsequent targeted drug development.
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2. Samanta A, Lufkin T, Kraus P. Intervertebral disc degeneration-Current therapeutic options and challenges. Front Public Health. 2023;11:1156749.
3. Mohd II, Teoh SL, Mohd NN, Mokhtar SA. Discogenic Low Back Pain: Anatomy, Pathophysiology, and Treatments of Intervertebral Disc Degeneration. Int J Mol Sci. 2022;24(1)
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7. Chao-Yang G, Peng C, Hai-Hong Z. Roles of NLRP3 inflammasome in intervertebral disc degeneration. Osteoarthr Cartilage. 2021;29(6):793-801.
8. Francisco V, Pino J, Gonzalez-Gay MA, Lago F, Karppinen J, Tervonen O, et al. A new immunometabolic perspective of intervertebral disc degeneration. Nat Rev Rheumatol. 2022;18(1):47-60.
9. Chen X, Wang Z, Deng R, Yan H, Liu X, Kang R. Intervertebral disc degeneration and inflammatory microenvironment: expression, pathology, and therapeutic strategies. Inflamm Res. 2023;72(9):1811-28.
10. Song C, Zhou Y, Cheng K, Liu F, Cai W, Zhou D, et al. Cellular senescence - Molecular mechanisms of intervertebral disc degeneration from an immune perspective. Biomed Pharmacother. 2023;162:114711.
11. Kampe A, Knebel A, Carlson R, Rohn K, Tipold A. Evaluation of the involvement of Th17-cells in the pathogenesis of canine spinal cord injury. Plos One. 2021;16(9):e0257442.
12. Hanaei S, Abdollahzade S, Sadr M, Mirbolouk MH, Fattahi E, Khoshnevisan A, et al. The role of interleukin 4 and IL-4RA in intervertebral disc degeneration: investigation of single nucleotide polymorphisms in genes and a systematic review & meta-analysis of IL-4 expression level. Brit J Neurosurg. 2020;34(1):66-71.
13. Lee S, Millecamps M, Foster DZ, Stone LS. Long-term histological analysis of innervation and macrophage infiltration in a mouse model of intervertebral disc injury-induced low back pain. J Orthop Res. 2020;38(6):1238-47.
14. Kawakubo A, Uchida K, Miyagi M, Nakawaki M, Satoh M, Sekiguchi H, et al. Investigation of resident and recruited macrophages following disc injury in mice. J Orthop Res. 2020;38(8):1703-9.
15. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7):e47.
16. Yu G. Gene Ontology Semantic Similarity Analysis Using GOSemSim. Methods Mol Biol. 2020;2117:207-15.
17. Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28(1):27-30.
18. Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R, et al. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 2023;51(D1):D638-46.
19. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498-504.
20. Barbie DA, Tamayo P, Boehm JS, Kim SY, Moody SE, Dunn IF, et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature. 2009;462(7269):108-12.
21. Hu S, Zhang C, Qian T, Bai Y, Chen L, Chen J, et al. Promoting Nrf2/Sirt3-Dependent Mitophagy Suppresses Apoptosis in Nucleus Pulposus Cells and Protects against Intervertebral Disc Degeneration. Oxid Med Cell Longev. 2021;2021:6694964.
22. Zhang X, Yang L, Gao F, Yuan Z, Lin X, Yao B, et al. Comparison of T1rho and T2* Relaxation Mapping in Patients with Different Grades of Disc Degeneration at 3T MR. Med Sci Monitor. 2015;21:1934-41.
23. Zhong B, Huang D, Ma K, Deng X, Shi D, Wu F, et al. Association of COL1A1 rs1800012 polymorphism with musculoskeletal degenerative diseases: a meta-analysis. Oncotarget. 2017;8(43):75488-99.
24. Fang W, Zhou X, Wang J, Xu L, Zhou L, Yu W, et al. Wogonin mitigates intervertebral disc degeneration through the Nrf2/ARE and MAPK signaling pathways. Int Immunopharmacol. 2018;65:539-49.
25. DiStefano TJ, Vaso K, Danias G, Chionuma HN, Weiser JR, Iatridis JC. Extracellular Vesicles as an Emerging Treatment Option for Intervertebral Disc Degeneration: Therapeutic Potential, Translational Pathways, and Regulatory Considerations. Adv Healthc Mater. 2022;11(5):e2100596.
26. Sampara P, Banala RR, Vemuri SK, Av GR, Gpv S. Understanding the molecular biology of intervertebral disc degeneration and potential gene therapy strategies for regeneration: a review. Gene Ther. 2018;25(2):67-82.
27. Koroth J, Buko EO, Abbott R, Johnson CP, Ogle BM, Stone LS, et al. Macrophages and Intervertebral Disc Degeneration. Int J Mol Sci. 2023;24(2)
28. Wu XT, Wang YX, Feng XM, Feng M, Sun HH. Update on the roles of macrophages in the degeneration and repair process of intervertebral discs. Joint Bone Spine. 2023;90(3):105514.
29. Yang H, Liu B, Liu Y, He D, Xing Y, An Y, et al. Secreted Factors From Intervertebral Disc Cells and Infiltrating Macrophages Promote Degenerated Intervertebral Disc Catabolism. Spine. 2019;44(9):E520-9.
30. Guo W, Zhang B, Li Y, Duan HQ, Sun C, Xu YQ, et al. Gene expression profile identifies potential biomarkers for human intervertebral disc degeneration. Mol Med Rep. 2017;16(6):8665-72.
31. Ouyang ZH, Wang WJ, Yan YG, Wang B, Lv GH. The PI3K/Akt pathway: a critical player in intervertebral disc degeneration. Oncotarget. 2017;8(34):57870-81.
32. Tan Y, Yao X, Dai Z, Wang Y, Lv G. Bone morphogenetic protein 2 alleviated intervertebral disc degeneration through mediating the degradation of ECM and apoptosis of nucleus pulposus cells via the PI3K/Akt pathway. Int J Mol Med. 2019;43(1):583-92.
33. Chen W, Li S, Zhang F. Role of lncRNA XIST/microRNA-19/PTEN network in autophagy of nucleus pulposus cells in intervertebral disc degeneration via the PI3K/Akt signaling pathway. Cell Cycle. 2021;20(17):1629-41.
34. Wen X, Chen S, Chen X, Qiu H, Wang W, Zhang N, et al. ITGB5 promotes innate radiation resistance in pancreatic adenocarcinoma by promoting DNA damage repair and the MEK/ERK signaling pathway. Front Oncol. 2022;12:887068.
35. Zhang LY, Guo Q, Guan GF, Cheng W, Cheng P, Wu AH. Integrin Beta 5 Is a Prognostic Biomarker and Potential Therapeutic Target in Glioblastoma. Front Oncol. 2019;9:904.
36. Xu D, Li T, Wang R, Mu R. Expression and Pathogenic Analysis of Integrin Family Genes in Systemic Sclerosis. Front Med-Lausanne. 2021;8:674523.
37. Hou J, Ji J, Chen X, Cao H, Tan Y, Cui Y, et al. Alveolar epithelial cell-derived Sonic hedgehog promotes pulmonary fibrosis through OPN-dependent alternative macrophage activation. Febs J. 2021;288(11):3530-46.
38. Ma CJ, Liu X, Che L, Liu ZH, Samartzis D, Wang HQ. Stem Cell Therapies for Intervertebral Disc Degeneration: Immune Privilege Reinforcement by Fas/FasL Regulating Machinery. Curr Stem Cell Res T. 2015;10(4):285-95.
39. Song C, Cai W, Liu F, Cheng K, Guo D, Liu Z. An in-depth analysis of the immunomodulatory mechanisms of intervertebral disc degeneration. Jor Spine. 2022;5(4):e1233.
40. Geiss A, Larsson K, Rydevik B, Takahashi I, Olmarker K. Autoimmune properties of nucleus pulposus: an experimental study in pigs. Spine. 2007;32(2):168-73.
41. Shi ZW, Zhu L, Song ZR, Liu TJ, Hao DJ. Roles of p38 MAPK signalling in intervertebral disc degeneration. Cell Proliferat. 2023;56(8):e13438.
42. Rohanifar M, Clayton SW, Easson G, Patil DS, Lee F, Jing L, et al. Single Cell RNA-Sequence Analyses Reveal Uniquely Expressed Genes and Heterogeneous Immune Cell Involvement in the Rat Model of Intervertebral Disc Degeneration. Appl Sci-Basel. 2022;12(16)
43. Zhou H, Liu C, Hu F, Shen C, Shen B, He W, et al. Increased levels of circulating granulocytic myeloid‑derived suppressor cells in lumbar disc herniation. Exp Ther Med. 2023;26(2):367.
44. Schonauer R, Els-Heindl S, Beck-Sickinger AG. Adrenomedullin - new perspectives of a potent peptide hormone. J Pept Sci. 2017;23(7-8):472-85.
45. Lainchbury JG, Cooper GJ, Coy DH, Jiang NY, Lewis LK, Yandle TG, et al. Adrenomedullin: a hypotensive hormone in man. Clin Sci. 1997;92(5):467-72.
46. MacManus CF, Campbell EL, Keely S, Burgess A, Kominsky DJ, Colgan SP. Anti-inflammatory actions of adrenomedullin through fine tuning of HIF stabilization. Faseb J. 2011;25(6):1856-64.
47. Elsasser TH, Kahl S. Adrenomedullin has multiple roles in disease stress: development and remission of the inflammatory response. Microsc Res Techniq. 2002;57(2):120-9.
48. Veglia F, Sanseviero E, Gabrilovich DI. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat Rev Immunol. 2021;21(8):485-98.
49. Wynn TA, Vannella KM. Macrophages in Tissue Repair, Regeneration, and Fibrosis. Immunity. 2016;44(3):450-62.
50. Robinson WH, Lepus CM, Wang Q, Raghu H, Mao R, Lindstrom TM, et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat Rev Rheumatol. 2016;12(10):580-92.
51. Ishikawa LLW, Colavite PM, Fraga-Silva TFDC, Mimura LAN, Franca TGD, Zorzella-Pezavento SFG, et al. Vitamin D Deficiency and Rheumatoid Arthritis. Clin Rev Allerg Immu. 2017;52(3):373-88.
52. Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14(10):576-90.
53. Balogun S, Scott D, Aitken D. Association between sarcopenic obesity and knee osteoarthritis: A narrative review. Osteoarthr Cartil Open. 2024;6(3):100489.
2. Samanta A, Lufkin T, Kraus P. Intervertebral disc degeneration-Current therapeutic options and challenges. Front Public Health. 2023;11:1156749.
3. Mohd II, Teoh SL, Mohd NN, Mokhtar SA. Discogenic Low Back Pain: Anatomy, Pathophysiology, and Treatments of Intervertebral Disc Degeneration. Int J Mol Sci. 2022;24(1)
4. Liang H, Luo R, Li G, Zhang W, Song Y, Yang C. The Proteolysis of ECM in Intervertebral Disc Degeneration. Int J Mol Sci. 2022;23(3)
5. Lyu FJ, Cui H, Pan H, Mc CK, Cao X, Iatridis JC, et al. Painful intervertebral disc degeneration and inflammation: from laboratory evidence to clinical interventions. Bone Res. 2021;9(1):7.
6. Zhang HJ, Liao HY, Bai DY, Wang ZQ, Xie XW. MAPK /ERK signaling pathway: A potential target for the treatment of intervertebral disc degeneration. Biomed Pharmacother. 2021;143:112170.
7. Chao-Yang G, Peng C, Hai-Hong Z. Roles of NLRP3 inflammasome in intervertebral disc degeneration. Osteoarthr Cartilage. 2021;29(6):793-801.
8. Francisco V, Pino J, Gonzalez-Gay MA, Lago F, Karppinen J, Tervonen O, et al. A new immunometabolic perspective of intervertebral disc degeneration. Nat Rev Rheumatol. 2022;18(1):47-60.
9. Chen X, Wang Z, Deng R, Yan H, Liu X, Kang R. Intervertebral disc degeneration and inflammatory microenvironment: expression, pathology, and therapeutic strategies. Inflamm Res. 2023;72(9):1811-28.
10. Song C, Zhou Y, Cheng K, Liu F, Cai W, Zhou D, et al. Cellular senescence - Molecular mechanisms of intervertebral disc degeneration from an immune perspective. Biomed Pharmacother. 2023;162:114711.
11. Kampe A, Knebel A, Carlson R, Rohn K, Tipold A. Evaluation of the involvement of Th17-cells in the pathogenesis of canine spinal cord injury. Plos One. 2021;16(9):e0257442.
12. Hanaei S, Abdollahzade S, Sadr M, Mirbolouk MH, Fattahi E, Khoshnevisan A, et al. The role of interleukin 4 and IL-4RA in intervertebral disc degeneration: investigation of single nucleotide polymorphisms in genes and a systematic review & meta-analysis of IL-4 expression level. Brit J Neurosurg. 2020;34(1):66-71.
13. Lee S, Millecamps M, Foster DZ, Stone LS. Long-term histological analysis of innervation and macrophage infiltration in a mouse model of intervertebral disc injury-induced low back pain. J Orthop Res. 2020;38(6):1238-47.
14. Kawakubo A, Uchida K, Miyagi M, Nakawaki M, Satoh M, Sekiguchi H, et al. Investigation of resident and recruited macrophages following disc injury in mice. J Orthop Res. 2020;38(8):1703-9.
15. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7):e47.
16. Yu G. Gene Ontology Semantic Similarity Analysis Using GOSemSim. Methods Mol Biol. 2020;2117:207-15.
17. Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28(1):27-30.
18. Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R, et al. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 2023;51(D1):D638-46.
19. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498-504.
20. Barbie DA, Tamayo P, Boehm JS, Kim SY, Moody SE, Dunn IF, et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature. 2009;462(7269):108-12.
21. Hu S, Zhang C, Qian T, Bai Y, Chen L, Chen J, et al. Promoting Nrf2/Sirt3-Dependent Mitophagy Suppresses Apoptosis in Nucleus Pulposus Cells and Protects against Intervertebral Disc Degeneration. Oxid Med Cell Longev. 2021;2021:6694964.
22. Zhang X, Yang L, Gao F, Yuan Z, Lin X, Yao B, et al. Comparison of T1rho and T2* Relaxation Mapping in Patients with Different Grades of Disc Degeneration at 3T MR. Med Sci Monitor. 2015;21:1934-41.
23. Zhong B, Huang D, Ma K, Deng X, Shi D, Wu F, et al. Association of COL1A1 rs1800012 polymorphism with musculoskeletal degenerative diseases: a meta-analysis. Oncotarget. 2017;8(43):75488-99.
24. Fang W, Zhou X, Wang J, Xu L, Zhou L, Yu W, et al. Wogonin mitigates intervertebral disc degeneration through the Nrf2/ARE and MAPK signaling pathways. Int Immunopharmacol. 2018;65:539-49.
25. DiStefano TJ, Vaso K, Danias G, Chionuma HN, Weiser JR, Iatridis JC. Extracellular Vesicles as an Emerging Treatment Option for Intervertebral Disc Degeneration: Therapeutic Potential, Translational Pathways, and Regulatory Considerations. Adv Healthc Mater. 2022;11(5):e2100596.
26. Sampara P, Banala RR, Vemuri SK, Av GR, Gpv S. Understanding the molecular biology of intervertebral disc degeneration and potential gene therapy strategies for regeneration: a review. Gene Ther. 2018;25(2):67-82.
27. Koroth J, Buko EO, Abbott R, Johnson CP, Ogle BM, Stone LS, et al. Macrophages and Intervertebral Disc Degeneration. Int J Mol Sci. 2023;24(2)
28. Wu XT, Wang YX, Feng XM, Feng M, Sun HH. Update on the roles of macrophages in the degeneration and repair process of intervertebral discs. Joint Bone Spine. 2023;90(3):105514.
29. Yang H, Liu B, Liu Y, He D, Xing Y, An Y, et al. Secreted Factors From Intervertebral Disc Cells and Infiltrating Macrophages Promote Degenerated Intervertebral Disc Catabolism. Spine. 2019;44(9):E520-9.
30. Guo W, Zhang B, Li Y, Duan HQ, Sun C, Xu YQ, et al. Gene expression profile identifies potential biomarkers for human intervertebral disc degeneration. Mol Med Rep. 2017;16(6):8665-72.
31. Ouyang ZH, Wang WJ, Yan YG, Wang B, Lv GH. The PI3K/Akt pathway: a critical player in intervertebral disc degeneration. Oncotarget. 2017;8(34):57870-81.
32. Tan Y, Yao X, Dai Z, Wang Y, Lv G. Bone morphogenetic protein 2 alleviated intervertebral disc degeneration through mediating the degradation of ECM and apoptosis of nucleus pulposus cells via the PI3K/Akt pathway. Int J Mol Med. 2019;43(1):583-92.
33. Chen W, Li S, Zhang F. Role of lncRNA XIST/microRNA-19/PTEN network in autophagy of nucleus pulposus cells in intervertebral disc degeneration via the PI3K/Akt signaling pathway. Cell Cycle. 2021;20(17):1629-41.
34. Wen X, Chen S, Chen X, Qiu H, Wang W, Zhang N, et al. ITGB5 promotes innate radiation resistance in pancreatic adenocarcinoma by promoting DNA damage repair and the MEK/ERK signaling pathway. Front Oncol. 2022;12:887068.
35. Zhang LY, Guo Q, Guan GF, Cheng W, Cheng P, Wu AH. Integrin Beta 5 Is a Prognostic Biomarker and Potential Therapeutic Target in Glioblastoma. Front Oncol. 2019;9:904.
36. Xu D, Li T, Wang R, Mu R. Expression and Pathogenic Analysis of Integrin Family Genes in Systemic Sclerosis. Front Med-Lausanne. 2021;8:674523.
37. Hou J, Ji J, Chen X, Cao H, Tan Y, Cui Y, et al. Alveolar epithelial cell-derived Sonic hedgehog promotes pulmonary fibrosis through OPN-dependent alternative macrophage activation. Febs J. 2021;288(11):3530-46.
38. Ma CJ, Liu X, Che L, Liu ZH, Samartzis D, Wang HQ. Stem Cell Therapies for Intervertebral Disc Degeneration: Immune Privilege Reinforcement by Fas/FasL Regulating Machinery. Curr Stem Cell Res T. 2015;10(4):285-95.
39. Song C, Cai W, Liu F, Cheng K, Guo D, Liu Z. An in-depth analysis of the immunomodulatory mechanisms of intervertebral disc degeneration. Jor Spine. 2022;5(4):e1233.
40. Geiss A, Larsson K, Rydevik B, Takahashi I, Olmarker K. Autoimmune properties of nucleus pulposus: an experimental study in pigs. Spine. 2007;32(2):168-73.
41. Shi ZW, Zhu L, Song ZR, Liu TJ, Hao DJ. Roles of p38 MAPK signalling in intervertebral disc degeneration. Cell Proliferat. 2023;56(8):e13438.
42. Rohanifar M, Clayton SW, Easson G, Patil DS, Lee F, Jing L, et al. Single Cell RNA-Sequence Analyses Reveal Uniquely Expressed Genes and Heterogeneous Immune Cell Involvement in the Rat Model of Intervertebral Disc Degeneration. Appl Sci-Basel. 2022;12(16)
43. Zhou H, Liu C, Hu F, Shen C, Shen B, He W, et al. Increased levels of circulating granulocytic myeloid‑derived suppressor cells in lumbar disc herniation. Exp Ther Med. 2023;26(2):367.
44. Schonauer R, Els-Heindl S, Beck-Sickinger AG. Adrenomedullin - new perspectives of a potent peptide hormone. J Pept Sci. 2017;23(7-8):472-85.
45. Lainchbury JG, Cooper GJ, Coy DH, Jiang NY, Lewis LK, Yandle TG, et al. Adrenomedullin: a hypotensive hormone in man. Clin Sci. 1997;92(5):467-72.
46. MacManus CF, Campbell EL, Keely S, Burgess A, Kominsky DJ, Colgan SP. Anti-inflammatory actions of adrenomedullin through fine tuning of HIF stabilization. Faseb J. 2011;25(6):1856-64.
47. Elsasser TH, Kahl S. Adrenomedullin has multiple roles in disease stress: development and remission of the inflammatory response. Microsc Res Techniq. 2002;57(2):120-9.
48. Veglia F, Sanseviero E, Gabrilovich DI. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat Rev Immunol. 2021;21(8):485-98.
49. Wynn TA, Vannella KM. Macrophages in Tissue Repair, Regeneration, and Fibrosis. Immunity. 2016;44(3):450-62.
50. Robinson WH, Lepus CM, Wang Q, Raghu H, Mao R, Lindstrom TM, et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat Rev Rheumatol. 2016;12(10):580-92.
51. Ishikawa LLW, Colavite PM, Fraga-Silva TFDC, Mimura LAN, Franca TGD, Zorzella-Pezavento SFG, et al. Vitamin D Deficiency and Rheumatoid Arthritis. Clin Rev Allerg Immu. 2017;52(3):373-88.
52. Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14(10):576-90.
53. Balogun S, Scott D, Aitken D. Association between sarcopenic obesity and knee osteoarthritis: A narrative review. Osteoarthr Cartil Open. 2024;6(3):100489.
| Files | ||
| Issue | Vol 25 No 3 (2026) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v25i3.21260 | |
| Keywords | ||
| Bioinformatics analysis Gene differential expression Intervertebral disc degeneration Infiltration of immune cells Investigation of drug-gene interactions | ||
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How to Cite
1.
Lo H, Tsai C, Huang T. Comprehensive Analysis of Core Genes, Key Pathways, and Immune Infiltration in Intervertebral Disc Degeneration Using Machine Learning and Experimental Validation. Iran J Allergy Asthma Immunol. 2026;25(3):393-405.
