Skip to content
2000
Volume 29, Issue 1
  • ISSN: 1386-2073
  • E-ISSN: 1875-5402

Abstract

Introduction

The specific role of necroptosis in the pathogenesis of cataracts remains unclear. This study aimed to identify and validate the genes related to necroptosis in the development of cataracts through bioinformatics analysis.

Method

We utilized RNA sequencing data (GSE161701) from the Gene Expression Omnibus (GEO) database and employed R software to perform differential expression analysis of necroptosis-related genes (NRGs) in lens epithelial cells (LECs) under oxidative stress. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to evaluate the functions of necroptosis-related differentially expressed genes (NRDEGs) and their associated pathways. Additionally, a diagnostic model was established using LASSO regression to select hub genes, and protein-protein interaction (PPI) networks, mRNA-miRNA, and mRNA-drug regulatory networks were constructed. Immune infiltration analysis was performed using the xCell and CIBERSORT algorithms, and the differential expression of hub genes was validated in a UVB-induced rat cataract model using RT-qPCR and immunohistochemistry.

Results

The results indicated that oxidative stress promoted necroptosis in LECs, involving 86 NRDEGs and nine hub genes. GO and KEGG analyses revealed significant enrichment in necroptosis-associated pathways. Furthermore, we identified 58 mRNA-miRNA interactions and 131 potential molecular compounds or drugs. The immune infiltration analysis showed that certain immune cells exhibited significantly elevated expression in the cataract group, with notable correlations between some immune cells and hub genes. RT-qPCR and immunohistochemistry confirmed the expression of 9 hub genes and 3 key necroptosis genes. BAX, CXCL1, EPAS1, JUN, LRP1, RBM14, SERTAD1, and TNFAIP3 were highlighted as potential diagnostic and therapeutic targets.

Conclusion

This study identified key NRDEGs involved in the pathogenesis of cataracts under oxidative stress through bioinformatics analyses, potentially providing new targets and research directions for future cataract prevention and treatment.

© 2026 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cchts/10.2174/0113862073365864250312043532
2025-04-17
2026-03-04

  • From This Site

    /content/journals/cchts/10.2174/0113862073365864250312043532
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. LiuY.C. WilkinsM. KimT. MalyuginB. MehtaJ.S. Cataracts.Lancet20173901009460061210.1016/S0140‑6736(17)30544‑5 28242111
     [Google Scholar]
  2. MoreP.V. JagtapN.P. MusaleK.S. KadamM.A. BobadeS.S. PolD.K. Pathophysiology, diagnosis and management of cataract.Asian J. Pharma. Res.202414778210.52711/2231‑5691.2024.00012
     [Google Scholar]
  3. LeeB. AfshariN.A. ShawP.X. Oxidative stress and antioxidants in cataract development.Curr. Opin. Ophthalmol.2024351576310.1097/ICU.0000000000001009 37882550
     [Google Scholar]
  4. ChenW. LinH. ZhongX. LiuZ. GengY. XieC. ChenW. Discrepant expression of cytokines in inflammation- and age-related cataract patients.PLoS One2014910e10964710.1371/journal.pone.0109647 25303043
     [Google Scholar]
  5. RichardsonR.B. AinsburyE.A. PrescottC.R. LovicuF.J. Etiology of posterior subcapsular cataracts based on a review of risk factors including aging, diabetes, and ionizing radiation.Int. J. Radiat. Biol.202096111339136110.1080/09553002.2020.1812759 32897800
     [Google Scholar]
  6. HilliardA. MendoncaP. RussellT.D. SolimanK.F.A. The protective effects of flavonoids in cataract formation through the activation of Nrf2 and the inhibition of MMP-9.Nutrients20201212365110.3390/nu12123651 33261005
     [Google Scholar]
  7. SutkowyP. LesiewskaH. WoźniakA. MalukiewiczG. Inflammation-involved proteins in blood serum of cataract patients—a preliminary study.Biomedicines20231110260710.3390/biomedicines11102607 37892980
     [Google Scholar]
  8. LuA. DuanP. XieJ. GaoH. ChenM. GongY. LiJ. XuH. Recent progress and research trend of anti-cataract pharmacology therapy: A bibliometric analysis and literature review.Eur. J. Pharmacol.202293417529910.1016/j.ejphar.2022.175299 36181780
     [Google Scholar]
  9. LinkermannA. GreenD.R. Necroptosis.N. Engl. J. Med.2014370545546510.1056/NEJMra1310050 24476434
     [Google Scholar]
  10. LiuH. Expression and potential immune involvement of cuproptosis in kidney renal clear cell carcinoma.Cancer Genet.2023274-275212510.1016/j.cancergen.2023.03.002 36963335
     [Google Scholar]
  11. LiuH. TangT. Pan-cancer genetic analysis of cuproptosis and copper metabolism-related gene set.Front. Oncol.20221295229010.3389/fonc.2022.952290 36276096
     [Google Scholar]
  12. LiuH. TangT. Pan-cancer genetic analysis of disulfidptosis-related gene set.Cancer Genet.2023278-2799110310.1016/j.cancergen.2023.10.001 37879141
     [Google Scholar]
  13. ChanF.K.M. LuzN.F. MoriwakiK. Programmed necrosis in the cross talk of cell death and inflammation.Annu. Rev. Immunol.20153317910610.1146/annurev‑immunol‑032414‑112248 25493335
     [Google Scholar]
  14. ChenJ. KosR. GarssenJ. RedegeldF. Molecular insights into the mechanism of necroptosis: The necrosome as a potential therapeutic target.Cells2019812148610.3390/cells8121486 31766571
     [Google Scholar]
  15. RieglerA.N. BrissacT. Gonzalez-JuarbeN. OrihuelaC.J. Necroptotic cell death promotes adaptive immunity against colonizing pneumococci.Front. Immunol.20191061510.3389/fimmu.2019.00615 31019504
     [Google Scholar]
  16. BerthelootD. LatzE. FranklinB.S. Necroptosis, pyroptosis and apoptosis: An intricate game of cell death.Cell. Mol. Immunol.20211851106112110.1038/s41423‑020‑00630‑3 33785842
     [Google Scholar]
  17. ScarpelliniC. LlorcaR.A. LanthierC. KlejborowskaG. AugustynsK. The potential role of regulated cell death in dry eye diseases and ocular surface dysfunction.Int. J. Mol. Sci.202324173110.3390/ijms24010731 36614174
     [Google Scholar]
  18. GaoS. ZhangY. ZhangM. Targeting novel regulated cell death: Pyroptosis, necroptosis, and ferroptosis in diabetic retinopathy.Front. Cell Dev. Biol.20221093288610.3389/fcell.2022.932886 35813208
     [Google Scholar]
  19. KimG.N. HahY.S. SeongH. YooW.S. ChoiM.Y. ChoH.Y. YunS.P. KimS.J. The role of nuclear factor of activated T cells S in hyperosmotic stress-exposed human lens epithelial cells.Int. J. Mol. Sci.20212212629610.3390/ijms22126296 34208226
     [Google Scholar]
  20. HuangJ. YuW. HeQ. HeX. YangM. ChenW. HanW. Autophagy facilitates age-related cell apoptosis—a new insight from senile cataract.Cell Death Dis.20221313710.1038/s41419‑021‑04489‑8 35013122
     [Google Scholar]
  21. BarrettT. WilhiteS.E. LedouxP. EvangelistaC. KimI.F. TomashevskyM. MarshallK.A. PhillippyK.H. ShermanP.M. HolkoM. YefanovA. LeeH. ZhangN. RobertsonC.L. SerovaN. DavisS. SobolevaA. NCBI GEO: Archive for functional genomics data sets--update.Nucleic Acids Res.201341Database issueD991D995 23193258
     [Google Scholar]
  22. KhamenehC.S. RaziS. ShamdaniS. UzanG. NaserianS. Weighted correlation network analysis revealed novel long non-coding RNAs for colorectal cancer.Sci. Rep.2022121299010.1038/s41598‑022‑06934‑w 35194111
     [Google Scholar]
  23. FishilevichS. NudelR. RappaportN. HadarR. PlaschkesI. SteinI.T. RosenN. KohnA. TwikM. SafranM. LancetD. CohenD. GeneHancer: Genome-wide integration of enhancers and target genes in GeneCards.Database2017bax02810.1093/database/bax028 28605766
     [Google Scholar]
  24. LiberzonA. BirgerC. ThorvaldsdóttirH. GhandiM. MesirovJ.P. TamayoP. The molecular signatures database (MSigDB) hallmark gene set collection.Cell Syst.20151641742510.1016/j.cels.2015.12.004 26771021
     [Google Scholar]
  25. RitchieM.E. PhipsonB. WuD. HuY. LawC.W. ShiW. SmythG.K. limma powers differential expression analyses for RNA-sequencing and microarray studies.Nucleic Acids Res.2015437e4710.1093/nar/gkv007 25605792
     [Google Scholar]
  26. ConsortiumG. O Gene Ontology Consortium: Going forward.Nucleic Acids Res.201543Database issueD1049D1056 25428369
     [Google Scholar]
  27. KanehisaM. GotoS. KEGG: Kyoto encyclopedia of genes and genomes.Nucleic Acids Res.2000281273010.1093/nar/28.1.27 10592173
     [Google Scholar]
  28. YuG. WangL.G. HanY. HeQ.Y. clusterProfiler: An R package for comparing biological themes among gene clusters.OMICS201216528428710.1089/omi.2011.0118 22455463
     [Google Scholar]
  29. YuG. LiF. QinY. BoX. WuY. WangS. GOSemSim: An R package for measuring semantic similarity among GO terms and gene products.Bioinformatics201026797697810.1093/bioinformatics/btq064 20179076
     [Google Scholar]
  30. SubramanianA. TamayoP. MoothaV.K. MukherjeeS. EbertB.L. GilletteM.A. PaulovichA. PomeroyS.L. GolubT.R. LanderE.S. MesirovJ.P. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles.Proc. Natl. Acad. Sci. USA200510243155451555010.1073/pnas.0506580102 16199517
     [Google Scholar]
  31. HänzelmannS. CasteloR. GuinneyJ. GSVA: Gene set variation analysis for microarray and RNA-Seq data.BMC Bioinformatics2013141710.1186/1471‑2105‑14‑7 23323831
     [Google Scholar]
  32. EngebretsenS. BohlinJ. Statistical predictions with glmnet.Clin. Epigenetics201911112310.1186/s13148‑019‑0730‑1 31443682
     [Google Scholar]
  33. WakonigB. AuerspergA.M.I. O’HaraM. String-pulling in the Goffin’s cockatoo (Cacatua goffiniana).Learn. Behav.202149112413610.3758/s13420‑020‑00454‑1 33483939
     [Google Scholar]
  34. WangW. ZhangJ. WangY. XuY. ZhangS. Identifies microtubule-binding protein CSPP1 as a novel cancer biomarker associated with ferroptosis and tumor microenvironment.Comput. Struct. Biotechnol. J.2022203322333510.1016/j.csbj.2022.06.046 35832625
     [Google Scholar]
  35. ChenY. WangX. miRDB: An online database for prediction of functional microRNA targets.Nucleic Acids Res.202048D1D127D13110.1093/nar/gkz757 31504780
     [Google Scholar]
  36. CottoK.C. WagnerA.H. FengY.Y. KiwalaS. CoffmanA.C. SpiesG. WollamA. SpiesN.C. GriffithO.L. GriffithM. DGIdb 3.0: A redesign and expansion of the drug–gene interaction database.Nucleic Acids Res.201846D1D1068D107310.1093/nar/gkx1143 29156001
     [Google Scholar]
  37. DvirAran ZchengHu ButteA.J. xCell: Digitally Portraying the Tissue Cellular Heterogeneity Landscape.Genome Biol.2017181220
     [Google Scholar]
  38. NewmanA.M. SteenC.B. LiuC.L. GentlesA.J. ChaudhuriA.A. SchererF. KhodadoustM.S. EsfahaniM.S. LucaB.A. SteinerD. DiehnM. AlizadehA.A. Determining cell type abundance and expression from bulk tissues with digital cytometry.Nat. Biotechnol.201937777378210.1038/s41587‑019‑0114‑2 31061481
     [Google Scholar]
  39. XiaoB. LiuL. LiA. XiangC. WangP. LiH. XiaoT. Identification and verification of immune-related gene prognostic signature based on ssGSEA for osteosarcoma.Front. Oncol.20201060762210.3389/fonc.2020.607622 33384961
     [Google Scholar]
  40. SchmittgenT.D. LivakK.J. Analyzing real-time PCR data by the comparative CT method.Nat. Protoc.2008361101110810.1038/nprot.2008.73 18546601
     [Google Scholar]
  41. AngM.J. AfshariN.A. Cataract and systemic disease: A review.Clin. Exp. Ophthalmol.202149211812710.1111/ceo.13892 33426783
     [Google Scholar]
  42. HsuehY.J. ChenY.N. TsaoY.T. ChengC.M. WuW.C. ChenH.C. The pathomechanism, antioxidant biomarkers, and treatment of oxidative stress-related eye diseases.Int. J. Mol. Sci.2022233125510.3390/ijms23031255 35163178
     [Google Scholar]
  43. JinX. JinH. ShiY. GuoY. ZhangH. Pyroptosis, a novel mechanism implicated in cataracts.Mol. Med. Rep.20181822277228510.3892/mmr.2018.9188 29956729
     [Google Scholar]
  44. WeiZ. HaoC. HuangfuJ. SrinivasaganR. ZhangX. FanX. Aging lens epithelium is susceptible to ferroptosis.Free Radic. Biol. Med.20211679410810.1016/j.freeradbiomed.2021.02.010 33722625
     [Google Scholar]
  45. RoyceG.H. Brown-BorgH.M. DeepaS.S. The potential role of necroptosis in inflammaging and aging.Geroscience201941679581110.1007/s11357‑019‑00131‑w 31721033
     [Google Scholar]
  46. LiuT. SunX. CaoZ. Shikonin-induced necroptosis in nasopharyngeal carcinoma cells via ROS overproduction and upregulation of RIPK1/RIPK3/MLKL expression.OncoTargets Ther.2019122605261410.2147/OTT.S200740 31118661
     [Google Scholar]
  47. XiaY. ZhangY. ZhangJ. DuY. WangY. XuA. LiS. Cadmium exposure induces necroptosis of porcine spleen via ROS ‐mediated activation of STAT1/RIPK3 signaling pathway.Environ. Mol. Mutagen.202364738239210.1002/em.22565 37452679
     [Google Scholar]
  48. KorbeckiJ. BarczakK. GutowskaI. ChlubekD. Baranowska-BosiackaI. CXCL1: Gene, promoter, regulation of expression, mRNA stability, regulation of activity in the intercellular space.Int. J. Mol. Sci.202223279210.3390/ijms23020792 35054978
     [Google Scholar]
  49. JiangS. LiangJ. LiW. WangL. SongM. XuS. LiuG. DuQ. ZhaiD. TangL. YangY. ZhangL. ZhangB. The role of CXCL1/CXCR2 axis in neurological diseases.Int. Immunopharmacol.202312011033010.1016/j.intimp.2023.110330 37247498
     [Google Scholar]
  50. JiangJ. ShihanM.H. WangY. DuncanM.K. Lens epithelial cells initiate an inflammatory response following cataract surgery.Invest. Ophthalmol. Vis. Sci.201859124986499710.1167/iovs.18‑25067 30326070
     [Google Scholar]
  51. Syc-MazurekS.B. FernandesK.A. LibbyR.T. JUN is important for ocular hypertension-induced retinal ganglion cell degeneration.Cell Death Dis.201787e294510.1038/cddis.2017.338 28726785
     [Google Scholar]
  52. LiD.W.C. SpectorA. Hydrogen peroxide-induced expression of the proto-oncogenes, c-jun, c-fos and c-myc in rabbit lens epithelial cells.Mol. Cell. Biochem.19971731/2596910.1023/A:1006828402225 9278255
     [Google Scholar]
  53. MomtaziG. LambrechtB.N. NaranjoJ.R. SchockB.C. Regulators of A20 (TNFAIP3): New drug-able targets in inflammation.Am. J. Physiol. Lung Cell. Mol. Physiol.20193163L456L46910.1152/ajplung.00335.2018 30543305
     [Google Scholar]
  54. BaoZ. FanL. ZhaoL. XuX. LiuY. ChaoH. LiuN. YouY. LiuY. WangX. JiJ. Silencing of A20 aggravates neuronal death and inflammation after traumatic brain injury: A potential trigger of necroptosis.Front. Mol. Neurosci.20191222210.3389/fnmol.2019.00222 31607859
     [Google Scholar]
  55. OnizawaM. OshimaS. Schulze-TopphoffU. Oses-PrietoJ.A. LuT. TavaresR. ProdhommeT. DuongB. WhangM.I. AdvinculaR. AgelidisA. BarreraJ. WuH. BurlingameA. MalynnB.A. ZamvilS.S. MaA. The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis.Nat. Immunol.201516661862710.1038/ni.3172 25939025
     [Google Scholar]
  56. HanusJ. ZhangH. WangZ. LiuQ. ZhouQ. WangS. Induction of necrotic cell death by oxidative stress in retinal pigment epithelial cells.Cell Death Dis.2013412e96510.1038/cddis.2013.478 24336085
     [Google Scholar]
  57. HuS. ChangX. ZhuH. WangD. ChenG. PI3K mediates tumor necrosis factor induced-necroptosis through initiating RIP1-RIP3-MLKL signaling pathway activation.Cytokine202012915504610.1016/j.cyto.2020.155046 32114297
     [Google Scholar]
  58. CaoM. ChenF. XieN. CaoM.Y. ChenP. LouQ. ZhaoY. HeC. ZhangS. SongX. SunY. ZhuW. MouL. LuanS. GaoH. c-Jun N-terminal kinases differentially regulate TNF- and TLRs-mediated necroptosis through their kinase-dependent and -independent activities.Cell Death Dis.2018912114010.1038/s41419‑018‑1189‑2 30442927
     [Google Scholar]
  59. LiL. ChenW. LiangY. MaH. LiW. ZhouZ. LiJ. DingY. RenJ. LinJ. HanF. WuJ. HanJ. The Gβγ-Src signaling pathway regulates TNF-induced necroptosis via control of necrosome translocation.Cell Res.201424441743210.1038/cr.2014.17 24513853
     [Google Scholar]
  60. TianX. WeiJ. Sestrin 2 protects human lens epithelial cells from oxidative stress and apoptosis induced by hydrogen peroxide by regulating the mTOR/Nrf2 pathway.Int. J. Immunopathol. Pharmacol.2024380394632024123474110.1177/03946320241234741 38379215
     [Google Scholar]
  61. XuD. ZhuH. FuQ. XuS. SunW. ChenG. LvX. Ketamine delays progression of oxidative and damaged cataract through regulating HMGB-1/NF-κB in lens epithelial cells.Immunopharmacol. Immunotoxicol.201840430330810.1080/08923973.2018.1478851 30111205
     [Google Scholar]
  62. LiuX.J. WangY.Q. ShangS.Q. XuS. GuoM. TMT induces apoptosis and necroptosis in mouse kidneys through oxidative stress-induced activation of the NLRP3 inflammasome.Ecotoxicol. Environ. Saf.202223011316710.1016/j.ecoenv.2022.113167 34995909
     [Google Scholar]
  63. WangK. LiuH. SunW. GuoJ. JiangZ. XuS. MiaoZ. Eucalyptol alleviates avermectin exposure-induced apoptosis and necroptosis of grass carp hepatocytes by regulating ROS/NLRP3 axis.Aquat. Toxicol.202326410673910.1016/j.aquatox.2023.106739 37918148
     [Google Scholar]
  64. GuoY. GuoC. ZhangJ. NingX. YanH. The protective mechanism of Grx2 in ultraviolet-B (UVB)-induced cataract formation.Biochem. Biophys. Res. Commun.202261310711210.1016/j.bbrc.2022.04.056 35550196
     [Google Scholar]
  65. Borges-RodríguezY. Morales-CuetoR. Rivillas-AcevedoL. Effect of the ultraviolet radiation on the lens.Curr. Protein Pept. Sci.202324321522810.2174/1389203724666230106161436 36617712
     [Google Scholar]
  66. LiuH. GuoZ. WangP. Genetic expression in cancer research: Challenges and complexity.Gene Rep.20243710204210.1016/j.genrep.2024.102042
     [Google Scholar]
  67. LiuH. LiY. KarsidagM. TuT. WangP. Technical and biological biases in bulk transcriptomic data mining for cancer research.J. Cancer2025161344310.7150/jca.100922 39744578
     [Google Scholar]
/content/journals/cchts/10.2174/0113862073365864250312043532
Loading
Identification of the Role of Necroptosis-Related Genes in the Oxidative Damage of Lens Epithelial Cells and Validation in Ultraviolet B-induced Cataract in Rats
Comb Chem High Throughput Screen 29, 122 (2026); https://doi.org/10.2174/0113862073365864250312043532
/content/journals/cchts/10.2174/0113862073365864250312043532
/content/journals/cchts/10.2174/0113862073365864250312043532
Loading

Data & Media loading...

Supplements

Supplementary Fig. . Normalization of GSE161701 dataset. Supplementary Fig. . KEGG enrichment pathway map. Supplementary Fig. . ROC curves and AUC of the nine hub genes. Supplementary Table . Cataract dataset information list. Supplementary Table . Necroptosis-related differentially expressed genes. Supplementary Table 3. GO enrichment analysis results of NRDEGs. Supplementary Table . KEGG enrichment analysis results of NRDEGs. Supplementary Table . GSEA analysis of the GSE161701 dataset. Supplementary Table . GSVA analysis of the GSE161701 dataset. Supplementary Table . mRNA-miRNA interaction network nodes. Supplementary Table . mRNA-drug interaction network nodes.

file format download Download

  • Article Type:     Research Article
Keyword(s): cataract; GEO; LASSO regression; lens epithelial cells; Necroptosis; necroptosis-related genes; oxidative damage; programmed cell death

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test