{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:03:36Z","timestamp":1790701416708,"version":"4.1.0"},"reference-count":31,"publisher":"IMR Press","issue":"9","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: PANoptosis-related transcriptional programs may contribute to pediatric ulcerative colitis (UC), but the genes most consistently associated with disease activity and epithelial injury remain uncertain. Methods: Public transcriptomic cohorts were integrated with machine-learning feature selection, treatment-response analyses, immune cell deconvolution, molecular clustering, and two-sample Mendelian randomization (MR). Transglutaminase 2 (TGM2) expression was examined in colonic specimens from six pediatric patients with UC and six controls. TGM2 knockdown was evaluated in lipopolysaccharide-stimulated HT29 cells using inflammatory gene analysis, tight junction protein measurements, RNA sequencing, and MAPK signaling assays. Results: A total of 17 differentially expressed PANoptosis-related genes were identified, and CCL2, JAK3, and TGM2 were prioritized as candidate genes. In the external GSE126124 cohort, TGM2 yielded an area under the curve of 0.918 in colonic tissue and 0.744 in peripheral blood. TGM2 expression was associated with disease activity, inflammatory cell estimates, barrier-related gene expression, and treatment response. Six single-nucleotide polymorphisms (SNPs) were included in the MR analysis. The inverse-variance weighted estimate was significant (odds ratio 1.486, 95% confidence interval 1.055\u20132.092; p = 0.023), whereas the other four methods were not significant. In LPS-stimulated HT29 cells, TGM2 knockdown was accompanied by lower TNF-\u03b1, IL-1\u03b2, and IL-6 expression, increased ZO-1, Occludin, and Claudin-3 abundance, and reduced ERK phosphorylation; substantial changes in JNK or p38 phosphorylation were not detected. Conclusion: TGM2 was identified as a candidate through PANoptosis-related bioinformatic screening. TGM2 expression was associated with pediatric UC activity and treatment response, whereas TGM2 knockdown was associated with reduced inflammatory gene expression, increased tight junction protein abundance, and lower ERK phosphorylation in LPS-stimulated HT29 cells. Functional involvement of TGM2 in PANoptosis and its mechanistic position within ERK signaling require further validation.<\/jats:p>","DOI":"10.31083\/fbl55382","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:21:51Z","timestamp":1790698911000},"source":"Crossref","is-referenced-by-count":0,"title":["TGM2 Activates the ERK Signaling Pathway to Disrupt Intestinal Barrier Function and Aggravate Colitis"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-8274-8997","authenticated-orcid":true,"given":"Hong","family":"Dai","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Huaibei People\u2019s Hospital, 235025 Huaibei, Anhui, China"},{"name":"Department of Pediatrics, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3028-4111","authenticated-orcid":true,"given":"Longfei","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufeng","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Huaibei People\u2019s Hospital, 235025 Huaibei, Anhui, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7198-6200","authenticated-orcid":true,"given":"Xiaojing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Ord\u00e1s I, Eckmann L, Talamini M, Baumgart DC, Sandborn WJ. Ulcerative colitis. Lancet (London, England). 2012; 380: 1606\u20131619.","DOI":"10.1016\/S0140-6736(12)60150-0"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Bouhuys M, Lexmond WS, van Rheenen PF. Pediatric Inflammatory Bowel Disease. Pediatrics. 2023; 151: e2022058037.","DOI":"10.1542\/peds.2022-058037"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"da Silva BC, Lyra AC, Rocha R, Santana GO. Epidemiology, demographic characteristics and prognostic predictors of ulcerative colitis. World Journal of Gastroenterology. 2014; 20: 9458\u20139467.","DOI":"10.3748\/wjg.v20.i28.9458"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Ashton JJ, Beattie RM. Inflammatory bowel disease: recent developments. Archives of Disease in Childhood. 2024; 109: 370\u2013376.","DOI":"10.1136\/archdischild-2023-325668"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Kobayashi T, Siegmund B, Le Berre C, Wei SC, Ferrante M, Shen B, et al. Ulcerative colitis. Nature Reviews. Disease Primers. 2020; 6: 74.","DOI":"10.1038\/s41572-020-0205-x"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Eisenstein M. Ulcerative colitis: towards remission. Nature. 2018; 563: S33.","DOI":"10.1038\/d41586-018-07276-2"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Ruemmele FM, Turner D. Differences in the management of pediatric and adult onset ulcerative colitis--lessons from the joint ECCO and ESPGHAN consensus guidelines for the management of pediatric ulcerative colitis. Journal of Crohn's & Colitis. 2014; 8: 1\u20134.","DOI":"10.1016\/j.crohns.2013.10.006"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"McCoubrey LE, Seegobin N, Sangfuang N, Moens F, Duyvejonck H, Declerck E, et al. The colon targeting efficacies of mesalazine medications and their impacts on the gut microbiome. Journal of Controlled Release : Official Journal of the Controlled Release Society. 2024; 369: 630\u2013641.","DOI":"10.1016\/j.jconrel.2024.04.016"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Kucharzik T, Koletzko S, Kannengiesser K, Dignass A. Ulcerative Colitis-Diagnostic and Therapeutic Algorithms. Deutsches Arzteblatt International. 2020; 117: 564\u2013574.","DOI":"10.3238\/arztebl.2020.0564"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Kakiuchi T, Yoshiura M. Vedolizumab as the First-Line of Biologicals for Pediatric Patients With Ulcerative Colitis. Clinical Therapeutics. 2022; 44: 1028\u20131032.","DOI":"10.1016\/j.clinthera.2022.06.004"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Penagini F, Cococcioni L, Pozzi E, Dilillo D, Rendo G, Mantegazza C, et al. Biological therapy in pediatric age. Pharmacological Research. 2020; 161: 105120.","DOI":"10.1016\/j.phrs.2020.105120"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Sun X, Yang Y, Meng X, Li J, Liu X, Liu H. PANoptosis: Mechanisms, biology, and role in disease. Immunological Reviews. 2024; 321: 246\u2013262.","DOI":"10.1111\/imr.13279"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Pandian N, Kanneganti TD. PANoptosis: A Unique Innate Immune Inflammatory Cell Death Modality. Journal of Immunology (Baltimore, Md. : 1950). 2022; 209: 1625\u20131633.","DOI":"10.4049\/jimmunol.2200508"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Pandeya A, Kanneganti TD. Therapeutic potential of PANoptosis: innate sensors, inflammasomes, and RIPKs in PANoptosomes. Trends in Molecular Medicine. 2024; 30: 74\u201388.","DOI":"10.1016\/j.molmed.2023.10.001"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Liu K, Wang M, Li D, Duc Duong NT, Liu Y, Ma J, et al. PANoptosis in autoimmune diseases interplay between apoptosis, necrosis, and pyroptosis. Frontiers in Immunology. 2024; 15: 1502855.","DOI":"10.3389\/fimmu.2024.1502855"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Koerner L, Wachsmuth L, Kumari S, Schwarzer R, Wagner T, Jiao H, et al. ZBP1 causes inflammation by inducing RIPK3-mediated necroptosis and RIPK1 kinase activity-independent apoptosis. Cell Death and Differentiation. 2024; 31: 938\u2013953.","DOI":"10.1038\/s41418-024-01321-6"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Banoth B, Tuladhar S, Karki R, Sharma BR, Briard B, Kesavardhana S, et al. ZBP1 promotes fungi-induced inflammasome activation and pyroptosis, apoptosis, and necroptosis (PANoptosis). The Journal of Biological Chemistry. 2020; 295: 18276\u201318283.","DOI":"10.1074\/jbc.RA120.015924"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Franz M, Rodriguez H, Lopes C, Zuberi K, Montojo J, Bader GD, et al. GeneMANIA update 2018. Nucleic Acids Research. 2018; 46: W60\u2013W64.","DOI":"10.1093\/nar\/gky311"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nature Communications. 2019; 10: 1523.","DOI":"10.1038\/s41467-019-09234-6"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Sandborn WJ, Sands BE, Vermeire S, Leung Y, Guo X, Modesto I, et al. Modified Mayo score versus Mayo score for evaluation of treatment efficacy in patients with ulcerative colitis: data from the tofacitinib OCTAVE program. Therapeutic Advances in Gastroenterology. 2022; 15: 17562848221136331.","DOI":"10.1177\/17562848221136331"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Chen B, Khodadoust MS, Liu CL, Newman AM, Alizadeh AA. Profiling Tumor Infiltrating Immune Cells with CIBERSORT. Methods in Molecular Biology (Clifton, N.J.). 2018; 1711: 243\u2013259.","DOI":"10.1007\/978-1-4939-7493-1_12"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Aran D, Hu Z, Butte AJ. xCell: digitally portraying the tissue cellular heterogeneity landscape. Genome Biology. 2017; 18: 220.","DOI":"10.1186\/s13059-017-1349-1"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Racle J, Gfeller D. EPIC: A Tool to Estimate the Proportions of Different Cell Types from Bulk Gene Expression Data. Methods in Molecular Biology (Clifton, N.J.). 2020; 2120: 233\u2013248.","DOI":"10.1007\/978-1-0716-0327-7_17"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Dehghan A. Genome-Wide Association Studies. Methods in Molecular Biology (Clifton, N.J.). 2018; 1793: 37\u201349.","DOI":"10.1007\/978-1-4939-7868-7_4"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Kuenzig ME, Fung SG, Marderfeld L, Mak JWY, Kaplan GG, Ng SC, et al. Twenty-first Century Trends in the Global Epidemiology of Pediatric-Onset Inflammatory Bowel Disease: Systematic Review. Gastroenterology. 2022; 162: 1147\u20131159.e4.","DOI":"10.1053\/j.gastro.2021.12.282"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Vuijk SA, Camman AE, de Ridder L. Considerations in Paediatric and Adolescent Inflammatory Bowel Disease. Journal of Crohn's & Colitis. 2024; 18: ii31\u2013ii45.","DOI":"10.1093\/ecco-jcc\/jjae087"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Yokoyama K, Yamamoto Y, Nambu R, Hagiwara SI, Abukawa D, Mizuochi T, et al. Safety and efficacy of vedolizumab in pediatric patients with ulcerative colitis: multicenter study in Japan. Journal of Gastroenterology and Hepatology. 2023; 38: 1107\u20131115.","DOI":"10.1111\/jgh.16246"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Tokita K, Shimizu H, Takeuchi I, Shimizu T, Arai K. Long-Term Efficacy and Safety of Golimumab for Ulcerative Colitis in a Pediatric Inflammatory Bowel Disease Center in Japan. Pediatric Gastroenterology, Hepatology & Nutrition. 2022; 25: 461\u2013472.","DOI":"10.5223\/pghn.2022.25.6.461"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Mansuri I, Wang S, Rufo PA, Liu E, Chan C, Bousvaros A. Efficacy and Safety of Sulfasalazine Suspension in Children With Ulcerative Colitis. Journal of Pediatric Gastroenterology and Nutrition. 2023; 76: 460\u2013467.","DOI":"10.1097\/MPG.0000000000003698"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"Greener JG, Kandathil SM, Moffat L, Jones DT. A guide to machine learning for biologists. Nature Reviews. Molecular Cell Biology. 2022; 23: 40\u201355.","DOI":"10.1038\/s41580-021-00407-0"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Wei W, Lu Y, Zhang M, Guo J, Zhang H. Identifying polyamine related biomarkers in diagnosis and treatment of ulcerative colitis by integrating bulk and single-cell sequencing data. Scientific Reports. 2024; 14: 18094.","DOI":"10.1038\/s41598-024-69322-6"}],"container-title":["Frontiers in Bioscience-Landmark"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/31\/9\/10.31083\/FBL55382","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:22:30Z","timestamp":1790698950000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/31\/9\/10.31083\/FBL55382"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,15]]},"references-count":31,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026]]}},"alternative-id":["S2768-6701(26)02268-9"],"URL":"https:\/\/doi.org\/10.31083\/fbl55382","relation":{},"ISSN":["2768-6701","2768-6698"],"issn-type":[{"value":"2768-6701","type":"print"},{"value":"2768-6698","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,15]]},"article-number":"55382"}}